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Sample records for tgcrnd8 mouse model

  1. Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

    Science.gov (United States)

    Colby-Milley, Jessica; Cavanagh, Chelsea; Jego, Sonia; Breitner, John C S; Quirion, Rémi; Adamantidis, Antoine

    2015-01-01

    In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.

  2. Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

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    Jessica Colby-Milley

    Full Text Available In addition to cognitive decline, individuals affected by Alzheimer's disease (AD can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz and low gamma range (20-50 Hz. Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg mice. We found that a lower dose (2 mg/kg of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.

  3. Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer's disease.

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    Hamm, Valentine; Héraud, Céline; Bott, Jean-Bastien; Herbeaux, Karine; Strittmatter, Carole; Mathis, Chantal; Goutagny, Romain

    2017-02-01

    Alzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Aβ levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and γ oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Aβ-independent. Our results could partly explain the limited efficacy of Aβ-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD.

  4. Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer’s disease

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    Hamm, Valentine; Héraud, Céline; Bott, Jean-Bastien; Herbeaux, Karine; Strittmatter, Carole; Mathis, Chantal; Goutagny, Romain

    2017-01-01

    Alzheimer’s disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Aβ levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and γ oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Aβ-independent. Our results could partly explain the limited efficacy of Aβ-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD. PMID:28275722

  5. A touch screen-automated cognitive test battery reveals impaired attention, memory abnormalities, and increased response inhibition in the TgCRND8 mouse model of Alzheimer's disease.

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    Romberg, Carola; Horner, Alexa E; Bussey, Timothy J; Saksida, Lisa M

    2013-03-01

    Transgenic mouse models of Alzheimer's disease (AD) with abundant β-amyloid develop memory impairments. However, multiple nonmnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals, but have not been routinely assessed in animal models. Here, we assessed the cognitive abilities of TgCRND8 mice-a widely used model of β-amyloid pathology-with a touch screen-based automated test battery. The test battery comprises highly translatable tests of multiple cognitive constructs impaired in human AD, such as memory, attention, and response control, as well as appropriate control tasks. We found that familial AD mutations affect not only memory, but also cause significant alterations of sustained attention and behavioral flexibility. Because changes in attention and response inhibition may affect performance on tests of other cognitive abilities including memory, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD. A more comprehensive phenotyping with specialized, multicomponent cognitive test batteries for mice might significantly advance translation from preclinical mouse studies to the clinic. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.

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    Cristina Grossi

    Full Text Available The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet, the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.

  7. Dietary composition modulates brain mass and solubilizable Aβ levels in a mouse model of aggressive Alzheimer's amyloid pathology

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    Buxbaum Joseph D

    2009-10-01

    Full Text Available Abstract Objective Alzheimer's disease (AD is a progressive neurodegenerative disease of the central nervous system (CNS. Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD. Methods From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1 reference (regular commercial chow; (2 high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate; (3 high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate; or (4 high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat. At age 18 wks, mice were sacrificed, and brains studied for (a wet weight; (b solubilizable Aβ content by ELISA; (c amyloid plaque burden; (d stereologic analysis of selected hippocampal subregions. Results Animals receiving a high fat diet showed increased brain levels of solubilizable Aβ, although we detected no effect on plaque burden. Unexpectedly, brains of mice fed a high protein/low carbohydrate diet were 5% lower in weight than brains from all other mice. In an effort to identify regions that might link loss of brain mass to cognitive function, we studied neuronal density and volume in hippocampal subregions. Neuronal density and volume in the hippocampal CA3 region of TgCRND8 mice tended to be lower in TgCRND8 mice receiving the high protein/low carbohydrate diet than in those receiving the regular chow. Neuronal density and volume were preserved in CA1 and in the dentate gyrus. Interpretation Dissociation of Aβ changes from brain mass changes raises the possibility that diet plays a role not only in modulating amyloidosis but also in

  8. Alterations in hippocampal network oscillations and theta-gamma coupling arise before Aβ overproduction in a mouse model of Alzheimer's disease.

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    Goutagny, Romain; Gu, Ning; Cavanagh, Chelsea; Jackson, Jesse; Chabot, Jean-Guy; Quirion, Rémi; Krantic, Slavica; Williams, Sylvain

    2013-06-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by memory impairments. Brain oscillatory activity is critical for cognitive function and is altered in AD patients. Recent evidence suggests that accumulation of soluble amyloid-beta (Aβ) induces reorganization of hippocampal networks. However, whether fine changes in network activity might be present at very early stages, before Aβ overproduction, remains to be determined. We therefore assessed whether theta and gamma oscillations and their cross-frequency coupling, which are known to be essential for normal memory function, were precociously altered in the hippocampus. Electrophysiological field potential recordings were performed using complete hippocampal preparations in vitro from young transgenic CRND8 mice, a transgenic mouse model of AD. Our results indicate that a significant proportion of 1-month-old TgCRND8 mice showed robust alterations of theta-gamma cross-frequency coupling in the principal output region of the hippocampus, the subiculum. In addition we showed that, compared to controls, these mice expressed negligible levels of Aβ. Finally, these network alterations were not due to genetic factors as 15-day-old animals did not exhibit theta-gamma coupling alterations. Thus, initial alterations in hippocampal network activity arise before Aβ accumulation and may represent an early biomarker for AD. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  9. Mouse Models of Arteriosclerosis

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    Xu, Qingbo

    2004-01-01

    Animal models are designed to be preliminary tools for better understanding of the pathogenesis, improvement in diagnosis, prevention, and therapy of arteriosclerosis in humans. Attracted by the well-defined genetic systems, a number of investigators have begun to use the mouse as an experimental system for arteriosclerosis research. Hundreds of inbred lines have been established, and the genetic map is relatively well defined, and both congenic strains and recombinant strains are available to facilitate genetic experimentation. Because arteriosclerosis is a complicated disease, which includes spontaneous (native) atherosclerosis, transplant arteriosclerosis, vein graft atherosclerosis, and angioplasty-induced restenosis, several mouse models for studying all types of arteriosclerosis have recently been established. Using these mouse models, much knowledge concerning the pathogenesis of the disease and therapeutic intervention has been gained, eg, origins of endothelial and smooth muscle cells in lesions of transplant and vein graft atherosclerosis. This review will not attempt to cover all aspects of mouse models, rather focus on models of arterial injuries, vein grafts, and transplant arteriosclerosis, by which the major progress in understanding the mechanisms of the disease has been made. This article will also point out (dis)advantages of a variety of models, and how the models can be appropriately chosen for different purposes of study. PMID:15215157

  10. Burn mouse models

    DEFF Research Database (Denmark)

    Calum, Henrik; Høiby, Niels; Moser, Claus

    2014-01-01

    Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third-degree b......Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third......-degree burn injury was induced with a hot-air blower. The third-degree burn was confirmed histologically. At 48 h, a decline in the concentration of peripheral blood leucocytes was observed in the group of mice with burn wound. The reduction was ascribed to the decline in concentration of polymorphonuclear...... neutrophil leucocytes and monocytes. When infecting the skin with Pseudomonas aeruginosa, a dissemination of bacteria was observed only in the burn wound group. Histological characterization of the skin showed an increased polymorphonuclear neutrophil granulocytes dominated inflammation in the group of mice...

  11. Mouse models for cancer research

    OpenAIRE

    Zhang, Wei; Moore, Lynette; Ji, Ping

    2011-01-01

    Mouse models of cancer enable researchers to learn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Journal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an ove...

  12. Mouse models of cataract

    Indian Academy of Sciences (India)

    2009-12-31

    Dec 31, 2009 ... Much of our knowledge about the function of genes in cataracts has been derived from the molecular analysis of spontaneous or induced mutations in the mouse. Mutations affecting the mouse lens can be identified easily by visual inspection, and a remarkable number of mutant lines have been ...

  13. Mouse Models of Rheumatoid Arthritis.

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    Caplazi, P; Baca, M; Barck, K; Carano, R A D; DeVoss, J; Lee, W P; Bolon, B; Diehl, L

    2015-09-01

    Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔ (ARE) mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients. © The Author(s) 2015.

  14. Mouse Models of Diabetic Neuropathy

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    O'Brien, Phillipe D.; Sakowski, Stacey A.; Feldman, Eva L.

    2014-01-01

    Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes and is associated with significant morbidity and mortality. DPN is characterized by progressive, distal-to-proximal degeneration of peripheral nerves that leads to pain, weakness, and eventual loss of sensation. The mechanisms underlying DPN pathogenesis are uncertain, and other than tight glycemic control in type 1 patients, there is no effective treatment. Mouse models of type 1 (T1DM) and type 2 diabetes (T2DM) are critical to improving our understanding of DPN pathophysiology and developing novel treatment strategies. In this review, we discuss the most widely used T1DM and T2DM mouse models for DPN research, with emphasis on the main neurologic phenotype of each model. We also discuss important considerations for selecting appropriate models for T1DM and T2DM DPN studies and describe the promise of novel emerging diabetic mouse models for DPN research. The development, characterization, and comprehensive neurologic phenotyping of clinically relevant mouse models for T1DM and T2DM will provide valuable resources for future studies examining DPN pathogenesis and novel therapeutic strategies. PMID:24615439

  15. Mouse models of Fanconi anemia

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    Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

    2009-07-31

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

  16. Effects of Huanglian-Jie-Du-Tang and its modified formula on the modulation of amyloid-β precursor protein processing in Alzheimer's disease models.

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    Siva Sundara Kumar Durairajan

    Full Text Available Huanglian-Jie-Du-Tang (HLJDT is a famous traditional Chinese herbal formula that has been widely used clinically to treat cerebral ischemia. Recently, we found that berberine, a major alkaloid compound in HLJDT, reduced amyloid-β (Aβ accumulation in an Alzheimer's disease (AD mouse model. In this study, we compared the effects of HLJDT, four single component herbs of HLJDT (Rhizoma coptidis (RC, Radix scutellariae (RS, Cortex phellodendri (CP and Fructus gardenia (FG and the modified formula of HLJDT (HLJDT-M, which is free of RS on the regulatory processing of amyloid-β precursor protein (APP in an in vitro model of AD. Here we show that treatment with HLJDT-M and its components RC, CP, and the main compound berberine on N2a mouse neuroblastoma cells stably expressing human APP with the Swedish mutation (N2a-SwedAPP significantly decreased the levels of full-length APP, phosphorylated APP at threonine 668, C-terminal fragments of APP, soluble APP (sAPP-α and sAPPβ-Swedish and reduced the generation of Aβ peptide in the cell lysates of N2a-SwedAPP. HLJDT-M showed more significant APP- and Aβ- reducing effects than berberine, RC or CP treatment alone. In contrast, HLJDT, its component RS and the main active compound of RS, baicalein, strongly increased the levels of all the metabolic products of APP in the cell lysates. The extract from FG, however, did not influence APP modulation. Interestingly, regular treatment of TgCRND8 APP transgenic mice with baicalein exacerbated the amyloid plaque burden, APP metabolism and Aβ production. Taken together, these data provide convincing evidence that HLJDT and baicalein treatment can increase the amyloidogenic metabolism of APP which is at least partly responsible for the baicalein-mediated Aβ plaque increase in the brains of TgCRND8 mice. On the other hand, HLJDT-M significantly decreased all the APP metabolic products including Aβ. Further study of HLJDT-M for therapeutic use in treating AD is

  17. Mouse Models of Gastric Cancer

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    Hayakawa, Yoku; Fox, James G.; Gonda, Tamas; Worthley, Daniel L.; Muthupalani, Sureshkumar; Wang, Timothy C.

    2013-01-01

    Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field. PMID:24216700

  18. Mouse models for methylmalonic aciduria.

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    Heidi L Peters

    Full Text Available Methylmalonic aciduria (MMA is a disorder of organic acid metabolism resulting from a functional defect of methylmalonyl-CoA mutase (MCM. MMA is associated with significant morbidity and mortality, thus therapies are necessary to help improve quality of life and prevent renal and neurological complications. Transgenic mice carrying an intact human MCM locus have been produced. Four separate transgenic lines were established and characterised as carrying two, four, five or six copies of the transgene in a single integration site. Transgenic mice from the 2-copy line were crossed with heterozygous knockout MCM mice to generate mice hemizygous for the human transgene on a homozygous knockout background. Partial rescue of the uniform neonatal lethality seen in homozygous knockout mice was observed. These rescued mice were significantly smaller than control littermates (mice with mouse MCM gene. Biochemically, these partial rescue mice exhibited elevated methylmalonic acid levels in urine, plasma, kidney, liver and brain tissue. Acylcarnitine analysis of blood spots revealed elevated propionylcarnitine levels. Analysis of mRNA expression confirms the human transgene is expressed at higher levels than observed for the wild type, with highest expression in the kidney followed closely by brain and liver. Partial rescue mouse fibroblast cultures had only 20% of the wild type MCM enzyme activity. It is anticipated that this humanised partial rescue mouse model of MMA will enable evaluation of long-term pathophysiological effects of elevated methylmalonic acid levels and be a valuable model for the investigation of therapeutic strategies, such as cell transplantation.

  19. Mouse Models of Tumor Immunotherapy.

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    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients. © 2016 Elsevier Inc. All rights reserved.

  20. Drug discovery in prostate cancer mouse models.

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    Valkenburg, Kenneth C; Pienta, Kenneth J

    2015-01-01

    The mouse is an important, though imperfect, organism with which to model human disease and to discover and test novel drugs in a preclinical setting. Many experimental strategies have been used to discover new biological and molecular targets in the mouse, with the hopes of translating these discoveries into novel drugs to treat prostate cancer in humans. Modeling prostate cancer in the mouse, however, has been challenging, and often drugs that work in mice have failed in human trials. The authors discuss the similarities and differences between mice and men; the types of mouse models that exist to model prostate cancer; practical questions one must ask when using a mouse as a model; and potential reasons that drugs do not often translate to humans. They also discuss the current value in using mouse models for drug discovery to treat prostate cancer and what needs are still unmet in field. With proper planning and following practical guidelines by the researcher, the mouse is a powerful experimental tool. The field lacks genetically engineered metastatic models, and xenograft models do not allow for the study of the immune system during the metastatic process. There remain several important limitations to discovering and testing novel drugs in mice for eventual human use, but these can often be overcome. Overall, mouse modeling is an essential part of prostate cancer research and drug discovery. Emerging technologies and better and ever-increasing forms of communication are moving the field in a hopeful direction.

  1. Mouse models for filovirus infections.

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    Bradfute, Steven B; Warfield, Kelly L; Bray, Mike

    2012-09-01

    The filoviruses marburg- and ebolaviruses can cause severe hemorrhagic fever (HF) in humans and nonhuman primates. Because many cases have occurred in geographical areas lacking a medical research infrastructure, most studies of the pathogenesis of filoviral HF, and all efforts to develop drugs and vaccines, have been carried out in biocontainment laboratories in non-endemic countries, using nonhuman primates (NHPs), guinea pigs and mice as animal models. NHPs appear to closely mirror filoviral HF in humans (based on limited clinical data), but only small numbers may be used in carefully regulated experiments; much research is therefore done in rodents. Because of their availability in large numbers and the existence of a wealth of reagents for biochemical and immunological testing, mice have become the preferred small animal model for filovirus research. Since the first experiments following the initial 1967 marburgvirus outbreak, wild-type or mouse-adapted viruses have been tested in immunocompetent or immunodeficient mice. In this paper, we review how these types of studies have been used to investigate the pathogenesis of filoviral disease, identify immune responses to infection and evaluate antiviral drugs and vaccines. We also discuss the strengths and weaknesses of murine models for filovirus research, and identify important questions for further study.

  2. The wobbler mouse, an ALS animal model

    DEFF Research Database (Denmark)

    Moser, Jakob Maximilian; Bigini, Paolo; Schmitt-John, Thomas

    2013-01-01

    This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking...

  3. Optimizing mouse models for precision cancer prevention.

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    Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory

    2016-03-01

    As cancer has become increasingly prevalent, cancer prevention research has evolved towards placing a greater emphasis on reducing cancer deaths and minimizing the adverse consequences of having cancer. 'Precision cancer prevention' takes into account the collaboration of intrinsic and extrinsic factors in influencing cancer incidence and aggressiveness in the context of the individual, as well as recognizing that such knowledge can improve early detection and enable more accurate discrimination of cancerous lesions. However, mouse models, and particularly genetically engineered mouse (GEM) models, have yet to be fully integrated into prevention research. In this Opinion article, we discuss opportunities and challenges for precision mouse modelling, including the essential criteria of mouse models for prevention research, representative success stories and opportunities for more refined analyses in future studies.

  4. Melatonin receptors: latest insights from mouse models

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    Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

    2014-01-01

    Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

  5. Pathology of Mouse Models of Accelerated Aging.

    Science.gov (United States)

    Harkema, L; Youssef, S A; de Bruin, A

    2016-03-01

    Progeroid mouse models display phenotypes in multiple organ systems that suggest premature aging and resemble features of natural aging of both mice and humans. The prospect of a significant increase in the global elderly population within the next decades has led to the emergence of "geroscience," which aims at elucidating the molecular mechanisms involved in aging. Progeroid mouse models are frequently used in geroscience as they provide insight into the molecular mechanisms that are involved in the highly complex process of natural aging. This review provides an overview of the most commonly reported nonneoplastic macroscopic and microscopic pathologic findings in progeroid mouse models (eg, osteoporosis, osteoarthritis, degenerative joint disease, intervertebral disc degeneration, kyphosis, sarcopenia, cutaneous atrophy, wound healing, hair loss, alopecia, lymphoid atrophy, cataract, corneal endothelial dystrophy, retinal degenerative diseases, and vascular remodeling). Furthermore, several shortcomings in pathologic analysis and descriptions of these models are discussed. Progeroid mouse models are valuable models for aging, but thorough knowledge of both the mouse strain background and the progeria-related phenotype is required to guide interpretation and translation of the pathology data. © The Author(s) 2016.

  6. Genetically Engineered Mouse Models in Cancer Research

    Science.gov (United States)

    Walrath, Jessica C.; Hawes, Jessica J.; Van Dyke, Terry; Reilly, Karlyne M.

    2012-01-01

    Mouse models of human cancer have played a vital role in understanding tumorigenesis and answering experimental questions that other systems cannot address. Advances continue to be made that allow better understanding of the mechanisms of tumor development, and therefore the identification of better therapeutic and diagnostic strategies. We review major advances that have been made in modeling cancer in the mouse and specific areas of research that have been explored with mouse models. For example, although there are differences between mice and humans, new models are able to more accurately model sporadic human cancers by specifically controlling timing and location of mutations, even within single cells. As hypotheses are developed in human and cell culture systems, engineered mice provide the most tractable and accurate test of their validity in vivo. For example, largely through the use of these models, the microenvironment has been established to play a critical role in tumorigenesis, since tumor development and the interaction with surrounding stroma can be studied as both evolve. These mouse models have specifically fueled our understanding of cancer initiation, immune system roles, tumor angiogenesis, invasion, and metastasis, and the relevance of molecular diversity observed among human cancers. Currently, these models are being designed to facilitate in vivo imaging to track both primary and metastatic tumor development from much earlier stages than previously possible. Finally, the approaches developed in this field to achieve basic understanding are emerging as effective tools to guide much needed development of treatment strategies, diagnostic strategies, and patient stratification strategies in clinical research. PMID:20399958

  7. Pathology of Mouse Models of Accelerated Aging

    NARCIS (Netherlands)

    Harkema, L; Youssef, S A; de Bruin, A

    2016-01-01

    Progeroid mouse models display phenotypes in multiple organ systems that suggest premature aging and resemble features of natural aging of both mice and humans. The prospect of a significant increase in the global elderly population within the next decades has led to the emergence of "geroscience,"

  8. Pathology of Mouse Models of Accelerated Aging

    NARCIS (Netherlands)

    Harkema, L.; Youssef, S. A.; de Bruin, A.

    Progeroid mouse models display phenotypes in multiple organ systems that suggest premature aging and resemble features of natural aging of both mice and humans. The prospect of a significant increase in the global elderly population within the next decades has led to the emergence of geroscience,

  9. Genetically engineered mouse models of prostate cancer

    NARCIS (Netherlands)

    Nawijn, Martijn C.; Bergman, Andreas M.; van der Poel, Henk G.

    Objectives: Mouse models of prostate cancer are used to test the contribution of individual genes to the transformation process, evaluate the collaboration between multiple genetic lesions observed in a single tumour, and perform preclinical intervention studies in prostate cancer research. Methods:

  10. Development of isotope labeling liquid chromatography mass spectrometry for mouse urine metabolomics: quantitative metabolomic study of transgenic mice related to Alzheimer's disease.

    Science.gov (United States)

    Peng, Jun; Guo, Kevin; Xia, Jianguo; Zhou, Jianjun; Yang, Jing; Westaway, David; Wishart, David S; Li, Liang

    2014-10-03

    Because of a limited volume of urine that can be collected from a mouse, it is very difficult to apply the common strategy of using multiple analytical techniques to analyze the metabolites to increase the metabolome coverage for mouse urine metabolomics. We report an enabling method based on differential isotope labeling liquid chromatography mass spectrometry (LC-MS) for relative quantification of over 950 putative metabolites using 20 μL of urine as the starting material. The workflow involves aliquoting 10 μL of an individual urine sample for ¹²C-dansylation labeling that target amines and phenols. Another 10 μL of aliquot was taken from each sample to generate a pooled sample that was subjected to ¹³C-dansylation labeling. The ¹²C-labeled individual sample was mixed with an equal volume of the ¹³C-labeled pooled sample. The mixture was then analyzed by LC-MS to generate information on metabolite concentration differences among different individual samples. The interday repeatability for the LC-MS runs was assessed, and the median relative standard deviation over 4 days was 5.0%. This workflow was then applied to a metabolomic biomarker discovery study using urine samples obtained from the TgCRND8 mouse model of early onset familial Alzheimer's disease (FAD) throughout the course of their pathological deposition of beta amyloid (Aβ). It was showed that there was a distinct metabolomic separation between the AD prone mice and the wild type (control) group. As early as 15-17 weeks of age (presymptomatic), metabolomic differences were observed between the two groups, and after the age of 25 weeks the metabolomic alterations became more pronounced. The metabolomic changes at different ages corroborated well with the phenotype changes in this transgenic mice model. Several useful candidate biomarkers including methionine, desaminotyrosine, taurine, N1-acetylspermidine, and 5-hydroxyindoleacetic acid were identified. Some of them were found in previous

  11. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2005-11-01

    Recent studies indicate that brain tumors, including glioblastoma multiforme, contain a subpopulation of cancer cells that display stem cell ...point to multinucleated giant cells ; and arrows in E and F indicate re- active astrocytes. J: Survival curves of Mut1, Mut2, Mut3, and p53 null (p53...in myelinating oligodendro- cytes (Figure 8J, arrows). These data support the model that, in vivo, glioblastoma cells have the stem cell capacity to

  12. Digenic Inheritance in Cystinuria Mouse Model.

    Directory of Open Access Journals (Sweden)

    Meritxell Espino

    Full Text Available Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months and late stage (8-months of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/- present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/- and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.

  13. Digenic Inheritance in Cystinuria Mouse Model

    Science.gov (United States)

    Espino, Meritxell; Font-Llitjós, Mariona; Vilches, Clara; Salido, Eduardo; Prat, Esther; López de Heredia, Miguel; Palacín, Manuel; Nunes, Virginia

    2015-01-01

    Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months) and late stage (8-months) of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/-) present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/-) and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients. PMID:26359869

  14. Genetically-defined ovarian cancer mouse models.

    Science.gov (United States)

    Morin, Patrice J; Weeraratna, Ashani T

    2016-01-01

    Epithelial ovarian cancer (EOC), the deadliest of gynaecological cancers, is a disease that remains difficult to detect early and treat efficiently. A significant challenge for researchers in the field is that the aetiology of EOC and the molecular pathways important for its development are poorly understood. Moreover, precursor lesions have not been readily identifiable, making the mechanisms of EOC progression difficult to delineate. In order to address these issues, several genetically-defined ovarian mouse models have been generated in the past 15 years. However, because of the recent suggestion that most EOCs may not originate from the ovarian surface 'epithelium', but from other tissues of the female genital tract, some models may need to be re-evaluated within this new paradigm. In this review, we examine several genetically-defined EOC models and discuss how the new paradigm may explain some of the features of these models. A better understanding of the strengths and limitations of the current EOC mouse models will undoubtedly allow us to utilize these tools to better understand the biology of the disease and develop new approaches for EOC prevention, detection, and treatment. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  15. Mouse Model of Burn Wound and Infection

    DEFF Research Database (Denmark)

    Calum, Henrik; Høiby, Niels; Moser, Claus

    2017-01-01

    The immunosuppression induced by thermal injury renders the burned victim susceptible to infection. A mouse model was developed to examine the immunosuppression, which was possible to induce even at a minor thermal insult of 6% total body surface area. After induction of the burn (48 hr) a depres......The immunosuppression induced by thermal injury renders the burned victim susceptible to infection. A mouse model was developed to examine the immunosuppression, which was possible to induce even at a minor thermal insult of 6% total body surface area. After induction of the burn (48 hr......) a depression of leukocytes in the peripheral blood was found of the burned mice. This depression was due to a reduction in the polymorphonuclear cells. The burned mice were not able to clear a Pseudomonas aeruginosa wound infection, since the infection spread to the blood as compared to mice only infected...... with P. aeruginosa subcutaneously. The burn model offers an opportunity to study infections under these conditions. The present model can also be used to examine new antibiotics and immune therapy. Our animal model resembling the clinical situation is useful in developing new treatments of burn wound...

  16. A humanized mouse model of tuberculosis.

    Directory of Open Access Journals (Sweden)

    Veronica E Calderon

    Full Text Available Mycobacterium tuberculosis (M.tb is the second leading infectious cause of death worldwide and the primary cause of death in people living with HIV/AIDS. There are several excellent animal models employed to study tuberculosis (TB, but many have limitations for reproducing human pathology and none are amenable to the direct study of HIV/M.tb co-infection. The humanized mouse has been increasingly employed to explore HIV infection and other pathogens where animal models are limiting. Our goal was to develop a small animal model of M.tb infection using the bone marrow, liver, thymus (BLT humanized mouse. NOD-SCID/γc(null mice were engrafted with human fetal liver and thymus tissue, and supplemented with CD34(+ fetal liver cells. Excellent reconstitution, as measured by expression of the human CD45 pan leukocyte marker by peripheral blood populations, was observed at 12 weeks after engraftment. Human T cells (CD3, CD4, CD8, as well as natural killer cells and monocyte/macrophages were all observed within the human leukocyte (CD45(+ population. Importantly, human T cells were functionally competent as determined by proliferative capacity and effector molecule (e.g. IFN-γ, granulysin, perforin expression in response to positive stimuli. Animals infected intranasally with M.tb had progressive bacterial infection in the lung and dissemination to spleen and liver from 2-8 weeks post infection. Sites of infection in the lung were characterized by the formation of organized granulomatous lesions, caseous necrosis, bronchial obstruction, and crystallization of cholesterol deposits. Human T cells were distributed throughout the lung, liver, and spleen at sites of inflammation and bacterial growth and were organized to the periphery of granulomas. These preliminary results demonstrate the potential to use the humanized mouse as a model of experimental TB.

  17. Development of Mouse Lung Deposition Models

    Science.gov (United States)

    2015-07-01

    deposition calculations in each strain of mouse: first by 3/1)TLC/FRC( , where FRC is the functional residual capacity or lung volume at rest and TLC is the...total lung capacity , to adjust airway dimensions to rest conditions, and second by 3/1T )2/V1( + , where TV is the tidal volume , to account for...geometry that was previously developed for humans, rats, and rhesus monkeys [6], [7]. Inputs to the model included lung geometry and volumes , and

  18. Mouse Genetic Models of Human Brain Disorders

    Directory of Open Access Journals (Sweden)

    Celeste eLeung

    2016-03-01

    Full Text Available Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioural phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases.

  19. The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

    Science.gov (United States)

    Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

    2015-01-01

    The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. Mouse Model Resources for Vision Research

    Directory of Open Access Journals (Sweden)

    Jungyeon Won

    2011-01-01

    Full Text Available The need for mouse models, with their well-developed genetics and similarity to human physiology and anatomy, is clear and their central role in furthering our understanding of human disease is readily apparent in the literature. Mice carrying mutations that alter developmental pathways or cellular function provide model systems for analyzing defects in comparable human disorders and for testing therapeutic strategies. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Two programs, the Eye Mutant Resource and the Translational Vision Research Models, focused on providing such models to the vision research community are described herein. Over 100 mutant lines from the Eye Mutant Resource and 60 mutant lines from the Translational Vision Research Models have been developed. The ocular diseases of the mutant lines include a wide range of phenotypes, including cataracts, retinal dysplasia and degeneration, and abnormal blood vessel formation. The mutations in disease genes have been mapped and in some cases identified by direct sequencing. Here, we report 3 novel alleles of Crxtvrm65, Rp1tvrm64, and Rpe65tvrm148 as successful examples of the TVRM program, that closely resemble previously reported knockout models.

  1. Transgenic Mouse Models of SV40-Induced Cancer.

    Science.gov (United States)

    Hudson, Amanda L; Colvin, Emily K

    2016-01-01

    The SV40 viral oncogene has been used since the 1970s as a reliable and reproducible method to generate transgenic mouse models. This seminal discovery has taught us an immense amount about how tumorigenesis occurs, and its success has led to the evolution of many mouse models of cancer. Despite the development of more modern and targeted approaches for developing genetically engineered mouse models of cancer, SV40-induced mouse models still remain frequently used today. This review discusses a number of cancer types in which SV40 mouse models of cancer have been developed and highlights their relevance and importance to preclinical research. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. Mouse models of colorectal cancer as preclinical models

    Science.gov (United States)

    Buczacki, Simon J.A.; Arends, Mark J.; Adams, David J.

    2015-01-01

    In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. PMID:26115037

  3. Cockayne syndrome pathogenesis: lessons from mouse models.

    Science.gov (United States)

    Jaarsma, Dick; van der Pluijm, Ingrid; van der Horst, Gijsbertus T J; Hoeijmakers, Jan H J

    2013-01-01

    Cockayne syndrome (CS) is a rare multisystem disorder characterized by cachectic dwarfism, nervous system abnormalities and features of premature aging. CS symptoms are associated with mutations in 5 genes, CSA, CSB, XPB, XPD and XPG encoding for proteins involved in the transcription-coupled subpathway of nucleotide excision DNA repair (NER). Mutant mice have been generated for all CS-associated genes and provide tools to examine how the cellular defects translate into CS symptoms. Mice deficient for Csa or Csb genetically mimic CS in man, and develop mild CS symptoms including reduced fat tissue, photoreceptor cell loss, and mild, but characteristic, nervous system pathology. These mild CS models are converted into severe CS models with short life span, progressive nervous system degeneration and cachectic dwarfism after simultaneous complete inactivation of global genome NER. A spectrum of mild-to-severe CS-like symptoms occurs in Xpb, Xpd, and Xpg mice that genetically mimic patients with a disorder that combines CS symptoms with another NER syndrome, xeroderma pigmentosum. In conclusion, CS mouse models mice develop a range of CS phenotypes and open promising perspectives for testing interventional approaches. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Transgenic Mouse Model of Chronic Beryllium Disease

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, Terry

    2009-05-26

    Animal models provide powerful tools for dissecting dose-response relationships and pathogenic mechanisms and for testing new treatment paradigms. Mechanistic research on beryllium exposure-disease relationships is severely limited by a general inability to develop a sufficient chronic beryllium disease animal model. Discovery of the Human Leukocyte Antigen (HLA) - DPB1Glu69 genetic susceptibility component of chronic beryllium disease permitted the addition of this human beryllium antigen presentation molecule to an animal genome which may permit development of a better animal model for chronic beryllium disease. Using FVB/N inbred mice, Drs. Rubin and Zhu, successfully produced three strains of HLA-DPB1 Glu 69 transgenic mice. Each mouse strain contains a haplotype of the HLA-DPB1 Glu 69 gene that confers a different magnitude of odds ratio (OR) of risk for chronic beryllium disease: HLA-DPB1*0401 (OR = 0.2), HLA-DPB1*0201 (OR = 15), HLA-DPB1*1701 (OR = 240). In addition, Drs. Rubin and Zhu developed transgenic mice with the human CD4 gene to permit better transmission of signals between T cells and antigen presenting cells. This project has maintained the colonies of these transgenic mice and tested the functionality of the human transgenes.

  5. Modeling Phenotypes of Tuberous Scerosis in the Mouse

    National Research Council Canada - National Science Library

    Shipley, James M

    2007-01-01

    The overall goal of this project is to generate a mouse model of the smooth muscle-related facets of tuberous sclerosis, specifically in an attempt to model the lung phenotype seen in a subset of TS...

  6. Modeling Phenotypes of Tuberous Sclerosis in the Mouse

    National Research Council Canada - National Science Library

    Shipley, James M

    2006-01-01

    The overall goal of this project is to generate a mouse model of the smooth muscle-related facets of tuberous sclerosis specifically in an attempt to model the lung phenotype seen in a subset of TS...

  7. Mouse models for gastric cancer: Matching models to biological questions

    Science.gov (United States)

    Poh, Ashleigh R; O'Donoghue, Robert J J

    2016-01-01

    Abstract Gastric cancer is the third leading cause of cancer‐related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late‐stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new‐targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre‐clinical development of new therapeutics. PMID:26809278

  8. Mouse models for human intestinal microbiota research: a critical evaluation

    NARCIS (Netherlands)

    Hugenholtz, Floor; de Vos, Willem M.

    2018-01-01

    Since the early days of the intestinal microbiota research, mouse models have been used frequently to study the interaction of microbes with their host. However, to translate the knowledge gained from mouse studies to a human situation, the major spatio-temporal similarities and differences between

  9. Mass spectrometry analysis of hepcidin peptides in experimental mouse models

    NARCIS (Netherlands)

    Tjalsma, H.; Laarakkers, C.M.; Swelm, R.P. van; Theurl, M.; Theurl, I.; Kemna, E.H.J.M.; Burgt, Y.E. van der; Venselaar, H.; Dutilh, B.E.; Russel, F.G.M.; Weiss, G.; Masereeuw, R.; Fleming, R.E.; Swinkels, D.W.

    2011-01-01

    The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse

  10. The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

    Science.gov (United States)

    Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

    2017-11-01

    Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR. ©2017 American Association for Cancer Research.

  11. Mig-6 Mouse Model of Endometrial Cancer.

    Science.gov (United States)

    Kim, Tae Hoon; Yoo, Jung-Yoon; Jeong, Jae-Wook

    2017-01-01

    Endometrial cancer is a frequently occurring gynecological disorder. Estrogen-dependent endometrioid carcinoma is the most common type of gynecological cancer. One of the major pathologic phenomena of endometrial cancer is the loss of estrogen (E2) and progesterone (P4) control over uterine epithelial cell proliferation. P4 antagonizes the growth-promoting properties of E2 in the uterus. P4 prevents the development of endometrial cancer associated with unopposed E2 by blocking E2 actions. Mitogen inducible gene 6 (Mig-6, Errfi1, RALT, or gene 33) is an immediate early response gene that can be induced by various mitogens and common chronic stress stimuli. Mig-6 has been identified as an important component of P4-mediated inhibition of E2 signaling in the uterus. Decreased expression of MIG-6 is observed in human endometrial carcinomas. Transgenic mice with Mig-6 ablation in the uterus develop endometrial hyperplasia and E2-dependent endometrial cancer. Thus, MIG-6 has a tumor suppressor function in endometrial tumorigenesis. The following discussion summarizes our current knowledge of Mig-6 mouse models and their role in understanding the molecular mechanisms of endometrial tumorigenesis and in the development of therapeutic approaches for endometrial cancer.

  12. Mouse models for studying the formation and propagation of prions.

    Science.gov (United States)

    Watts, Joel C; Prusiner, Stanley B

    2014-07-18

    Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities

    Science.gov (United States)

    Liu, Chunhong; Belichenko, Pavel V.; Zhang, Li; Fu, Dawei; Kleschevnikov, Alexander M.; Baldini, Antonio; Antonarakis, Stylianos E.; Mobley, William C.; Yu, Y. Eugene

    2011-01-01

    Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes. PMID:21865664

  14. Characterization of a pneumococcal meningitis mouse model

    Directory of Open Access Journals (Sweden)

    Mook-Kanamori Barry

    2012-03-01

    Full Text Available Abstract Background S. pneumoniae is the most common causative agent of meningitis, and is associated with high morbidity and mortality. We aimed to develop an integrated and representative pneumococcal meningitis mouse model resembling the human situation. Methods Adult mice (C57BL/6 were inoculated in the cisterna magna with increasing doses of S. pneumoniae serotype 3 colony forming units (CFU; n = 24, 104, 105, 106 and 107 CFU and survival studies were performed. Cerebrospinal fluid (CSF, brain, blood, spleen, and lungs were collected. Subsequently, mice were inoculated with 104 CFU S. pneumoniae serotype 3 and sacrificed at 6 (n = 6 and 30 hours (n = 6. Outcome parameters were bacterial outgrowth, clinical score, and cytokine and chemokine levels (using Luminex® in CSF, blood and brain. Meningeal inflammation, neutrophil infiltration, parenchymal and subarachnoidal hemorrhages, microglial activation and hippocampal apoptosis were assessed in histopathological studies. Results Lower doses of bacteria delayed onset of illness and time of death (median survival CFU 104, 56 hrs; 105, 38 hrs, 106, 28 hrs. 107, 24 hrs. Bacterial titers in brain and CSF were similar in all mice at the end-stage of disease independent of inoculation dose, though bacterial outgrowth in the systemic compartment was less at lower inoculation doses. At 30 hours after inoculation with 104 CFU of S. pneumoniae, blood levels of KC, IL6, MIP-2 and IFN- γ were elevated, as were brain homogenate levels of KC, MIP-2, IL-6, IL-1β and RANTES. Brain histology uniformly showed meningeal inflammation at 6 hours, and, neutrophil infiltration, microglial activation, and hippocampal apoptosis at 30 hours. Parenchymal and subarachnoidal and cortical hemorrhages were seen in 5 of 6 and 3 of 6 mice at 6 and 30 hours, respectively. Conclusion We have developed and validated a murine model of pneumococcal meningitis.

  15. Chlamydia pneumoniae infections in mouse models: relevance for atherosclerosis research

    NARCIS (Netherlands)

    de Kruif, Martijn D.; van Gorp, Eric C. M.; Keller, Tymen T.; Ossewaarde, Jacobus M.; ten Cate, Hugo

    2005-01-01

    Mouse models have been frequently used in the study of Chlamydia pneumoniae (also known as Chlamydophila pneumoniae) infections. This gram-negative obligate intracellular bacterium causes respiratory infections, followed by dissemination of the bacterium to various organs throughout the body,

  16. Mouse models to study dengue virus immunology and pathogenesis

    Directory of Open Access Journals (Sweden)

    Raphaël M. Zellweger

    2014-04-01

    Full Text Available The development of a compelling murine model of dengue virus (DENV infection has been challenging, because dengue virus clinical isolates do not readily replicate or cause pathology in immunocompetent mice. However, research using immunocompromised mice and/or mouse-adapted viruses allows to investigate questions that may be impossible to address in human studies. In this review, we discuss the potential strengths and limitations of existing mouse models of dengue disease. Human studies are descriptive by nature; moreover, the strain, time, and sequence of infection are often unknown. In contrast, in mice, the conditions of infection are well defined and a large number of experimental parameters can be varied at will. Therefore, mouse models offer an opportunity to experimentally test hypotheses that are based on epidemiological observations. In particular, gain-of-function or loss-of-function models can be established to assess how different components of the immune system (either alone or in combination contribute to protection or pathogenesis during secondary infections or after vaccination. In addition, mouse models have been used for pre-clinical testing of antiviral drug or for vaccine development studies. Conclusions based on mouse experiments must be extrapolated to DENV infection in humans with caution due to the inherent limitations of animal models. However, research in mouse models is a useful complement to in vitro and epidemiological data, and may delineate new areas that deserve attention during future human studies.

  17. A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

    OpenAIRE

    Reddy, Doodipala Samba; Gould, Jordan; Gangisetty, O.

    2012-01-01

    Catamenial epilepsy is caused by fluctuations in progesterone-derived GABAA receptor-modulating anticonvulsant neurosteroids, such as allopregnanolone, that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy by using the neurosteroid-withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels ar...

  18. A Mouse Model of Chronic West Nile Virus Disease.

    Directory of Open Access Journals (Sweden)

    Jessica B Graham

    2016-11-01

    Full Text Available Infection with West Nile virus (WNV leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

  19. Humanized mouse xenograft models: narrowing the tumor-microenvironment gap

    OpenAIRE

    Morton, J. Jason; Bird, Gregory; Refaeli, Yosef; Jimeno, Antonio

    2016-01-01

    Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highly immunodeficient mouse strains into which human immune systems can be engrafted can help bridge this gap. Humanized mice (HM) allow researchers to examine xenograft growth in th...

  20. No audible wheezing: nuggets and conundrums from mouse asthma models.

    Science.gov (United States)

    Boyce, Joshua A; Austen, K Frank

    2005-06-20

    Mouse models of T helper type 2 (Th2) cell-biased pulmonary inflammation have elucidated mechanisms of sensitization, cell traffic, and induced airway hyperresponsiveness (AHR). Nonetheless, most mice lack intrinsic AHR, a central property of human asthma, and disparities persist regarding the contributions of eosinophils and mast cells and the sensitivity to induced AHR in the commonly used mouse strains. We suggest that these discordances, reflecting methodological and genetic differences, may be informative for understanding heterogeneity of human asthma.

  1. Mouse Model of Human Hereditary Pancreatitis

    Science.gov (United States)

    2016-09-01

    trypsin-dependent pathway in pancreatitis and to begin testing therapeutic and preventive approaches. Mutations in the digestive enzyme trypsinogen...expression of mutant trypsinogens at the protein level, we will perform chromatographic analysis of the total trypsinogen fraction isolated from mouse...pancreata (Subtask 4a). This subtask has been delayed until homozygous animals could be generated. Homozygous animals are now available and chromatographic

  2. Novel Transgenic Mouse Model of Polycystic Kidney Disease.

    Science.gov (United States)

    Kito, Yusuke; Saigo, Chiemi; Takeuchi, Tamotsu

    2017-09-01

    Transmembrane protein 207 (TMEM207) is characterized as an important molecule for invasiveness of gastric signet-ring cell carcinoma cells. To clarify the pathobiological effects of TMEM207, we generated 13 transgenic mouse strains, designated C57BL/6-transgenic (Tg) (ITF-TMEM207), where the mouse Tmem207 is ectopically expressed under the proximal promoter of the murine intestinal trefoil factor gene. A C57BL/6-Tg (ITF-TMEM207) mouse strain unexpectedly exhibited a high incidence of spontaneous kidney cysts with histopathological features resembling human polycystic kidney disease, which were found in approximately all mice within 1 year. TMEM207 immunoreactivity was found in noncystic kidney tubules and in renal cysts of the transgenic mice. The ITF-TMEM207 construct was inserted into Mitf at chromosome 6. Cystic kidney was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse strains. Although several genetically manipulated animal models exist, this mouse strain harboring a genetic mutation in Mitf and overexpression of Tmem207 protein was not reported as a model of polycystic kidney disease until now. This study demonstrates that the C57BL/6-Tg (ITF-TMEM207) mouse may be a suitable model for understanding human polycystic kidney disease. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  3. Genomic responses in mouse models poorly mimic human inflammatory diseases

    Science.gov (United States)

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  4. Decerebrate mouse model for studies of the spinal cord circuits

    DEFF Research Database (Denmark)

    Meehan, Claire Francesca; Mayr, Kyle A; Manuel, Marin

    2017-01-01

    . The protocol also describes an example application for the protocol: the evocation of spontaneous and actively driven stepping, including optimization of these behaviors in decerebrate mice. The time taken to prepare the animal and perform a decerebration takes ∼2 h, and the mice are viable for up to 3-8 h......The adult decerebrate mouse model (a mouse with the cerebrum removed) enables the study of sensory-motor integration and motor output from the spinal cord for several hours without compromising these functions with anesthesia. For example, the decerebrate mouse is ideal for examining locomotor...... behavior using intracellular recording approaches, which would not be possible using current anesthetized preparations. This protocol describes the steps required to achieve a low-blood-loss decerebration in the mouse and approaches for recording signals from spinal cord neurons with a focus on motoneurons...

  5. Non-Transgenic Mouse Models of Kidney Disease.

    Science.gov (United States)

    Rabe, Michael; Schaefer, Franz

    2016-01-01

    Animal models are essential tools to understand the mechanisms underlying the development and progression of renal disease and to study potential therapeutic approaches. Recently, interventional models suitable to induce acute and chronic kidney disease in the mouse have become a focus of interest due to the wide availability of genetically engineered mouse lines. These models differ by their damaging mechanism (cell toxicity, immune mechanisms, surgical renal mass reduction, ischemia, hypertension, ureter obstruction etc.), functional and histomorphological phenotype and disease evolution. The susceptibility to a damaging mechanism often depends on strain and gender. The C57BL/6 strain, the most commonly used genetic background of transgenic mice, appears to be relatively resistant against developing glomerulosclerosis, proteinuria and hypertension. This review serves to provide a comprehensive overview of interventional mouse models of acute and chronic kidney disease. © 2016 S. Karger AG, Basel.

  6. Mouse Models for Campylobacter jejuni Colonization and Infection.

    Science.gov (United States)

    Stahl, Martin; Graef, Franziska A; Vallance, Bruce A

    2017-01-01

    Relevant animal models for Campylobacter jejuni infection have been difficult to establish due to C. jejuni's inability to cause disease in many common animal research models. Fortunately, recent work has proven successful in developing several new and relevant mouse models of C. jejuni infection, including the SIGIRR-deficient mouse strain that develops acute enterocolitis in response to C. jejuni. Here we describe how to properly infect mice with C. jejuni, as well as a number of accompanying histological techniques to aid in studying C. jejuni colonization and infection in mice.

  7. Mouse Models as Predictors of Human Responses: Evolutionary Medicine.

    Science.gov (United States)

    Uhl, Elizabeth W; Warner, Natalie J

    Mice offer a number of advantages and are extensively used to model human diseases and drug responses. Selective breeding and genetic manipulation of mice have made many different genotypes and phenotypes available for research. However, in many cases, mouse models have failed to be predictive. Important sources of the prediction problem have been the failure to consider the evolutionary basis for species differences, especially in drug metabolism, and disease definitions that do not reflect the complexity of gene expression underlying disease phenotypes. Incorporating evolutionary insights into mouse models allow for unique opportunities to characterize the effects of diet, different gene expression profiles, and microbiomics underlying human drug responses and disease phenotypes.

  8. A preclinical mouse model of invasive lobular breast cancer metastasis

    NARCIS (Netherlands)

    Doornebal, Chris W.; Klarenbeek, Sjoerd; Braumuller, Tanya M.; Klijn, Christiaan N.; Ciampricotti, Metamia; Hau, Cheei-Sing; Hollmann, Markus W.; Jonkers, Jos; de Visser, Karin E.

    2013-01-01

    Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous

  9. Mass spectrometry analysis of hepcidin peptides in experimental mouse models.

    Science.gov (United States)

    Tjalsma, Harold; Laarakkers, Coby M M; van Swelm, Rachel P L; Theurl, Milan; Theurl, Igor; Kemna, Erwin H; van der Burgt, Yuri E M; Venselaar, Hanka; Dutilh, Bas E; Russel, Frans G M; Weiss, Günter; Masereeuw, Rosalinde; Fleming, Robert E; Swinkels, Dorine W

    2011-03-08

    The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse Hepcidin-1 (Hep-1) and its paralogue Hepcidin-2 (Hep-2) at the peptide level. To this purpose, Fourier transform ion cyclotron resonance (FTICR) and tandem-MS was used for hepcidin identification, after which a time-of-flight (TOF) MS-based methodology was exploited to routinely determine Hep-1 and -2 levels in mouse serum and urine. This method was biologically validated by hepcidin assessment in: i) 3 mouse strains (C57Bl/6; DBA/2 and BABL/c) upon stimulation with intravenous iron and LPS, ii) homozygous Hfe knock out, homozygous transferrin receptor 2 (Y245X) mutated mice and double affected mice, and iii) mice treated with a sublethal hepatotoxic dose of paracetamol. The results showed that detection of Hep-1 was restricted to serum, whereas Hep-2 and its presumed isoforms were predominantly present in urine. Elevations in serum Hep-1 and urine Hep-2 upon intravenous iron or LPS were only moderate and varied considerably between mouse strains. Serum Hep-1 was decreased in all three hemochromatosis models, being lowest in the double affected mice. Serum Hep-1 levels correlated with liver hepcidin-1 gene expression, while acute liver damage by paracetamol depleted Hep-1 from serum. Furthermore, serum Hep-1 appeared to be an excellent indicator of splenic iron accumulation. In conclusion, Hep-1 and Hep-2 peptide responses in experimental mouse agree with the known biology of hepcidin mRNA regulators, and their measurement can now be implemented in experimental mouse models to provide novel insights in post-transcriptional regulation, hepcidin function, and kinetics.

  10. Mass spectrometry analysis of hepcidin peptides in experimental mouse models.

    Directory of Open Access Journals (Sweden)

    Harold Tjalsma

    Full Text Available The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse Hepcidin-1 (Hep-1 and its paralogue Hepcidin-2 (Hep-2 at the peptide level. To this purpose, Fourier transform ion cyclotron resonance (FTICR and tandem-MS was used for hepcidin identification, after which a time-of-flight (TOF MS-based methodology was exploited to routinely determine Hep-1 and -2 levels in mouse serum and urine. This method was biologically validated by hepcidin assessment in: i 3 mouse strains (C57Bl/6; DBA/2 and BABL/c upon stimulation with intravenous iron and LPS, ii homozygous Hfe knock out, homozygous transferrin receptor 2 (Y245X mutated mice and double affected mice, and iii mice treated with a sublethal hepatotoxic dose of paracetamol. The results showed that detection of Hep-1 was restricted to serum, whereas Hep-2 and its presumed isoforms were predominantly present in urine. Elevations in serum Hep-1 and urine Hep-2 upon intravenous iron or LPS were only moderate and varied considerably between mouse strains. Serum Hep-1 was decreased in all three hemochromatosis models, being lowest in the double affected mice. Serum Hep-1 levels correlated with liver hepcidin-1 gene expression, while acute liver damage by paracetamol depleted Hep-1 from serum. Furthermore, serum Hep-1 appeared to be an excellent indicator of splenic iron accumulation. In conclusion, Hep-1 and Hep-2 peptide responses in experimental mouse agree with the known biology of hepcidin mRNA regulators, and their measurement can now be implemented in experimental mouse models to provide novel insights in post-transcriptional regulation, hepcidin function, and kinetics.

  11. Mass Spectrometry Analysis of Hepcidin Peptides in Experimental Mouse Models

    Science.gov (United States)

    van Swelm, Rachel P. L.; Theurl, Milan; Theurl, Igor; Kemna, Erwin H.; van der Burgt, Yuri E. M.; Venselaar, Hanka; Dutilh, Bas E.; Russel, Frans G. M.; Weiss, Günter; Masereeuw, Rosalinde; Fleming, Robert E.; Swinkels, Dorine W.

    2011-01-01

    The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse Hepcidin-1 (Hep-1) and its paralogue Hepcidin-2 (Hep-2) at the peptide level. To this purpose, fourier transform ion cyclotron resonance (FTICR) and tandem-MS was used for hepcidin identification, after which a time-of-flight (TOF) MS-based methodology was exploited to routinely determine Hep-1 and -2 levels in mouse serum and urine. This method was biologically validated by hepcidin assessment in: i) 3 mouse strains (C57Bl/6; DBA/2 and BABL/c) upon stimulation with intravenous iron and LPS, ii) homozygous Hfe knock out, homozygous transferrin receptor 2 (Y245X) mutated mice and double affected mice, and iii) mice treated with a sublethal hepatotoxic dose of paracetamol. The results showed that detection of Hep-1 was restricted to serum, whereas Hep-2 and its presumed isoforms were predominantly present in urine. Elevations in serum Hep-1 and urine Hep-2 upon intravenous iron or LPS were only moderate and varied considerably between mouse strains. Serum Hep-1 was decreased in all three hemochromatosis models, being lowest in the double affected mice. Serum Hep-1 levels correlated with liver hepcidin-1 gene expression, while acute liver damage by paracetamol depleted Hep-1 from serum. Furthermore, serum Hep-1 appeared to be an excellent indicator of splenic iron accumulation. In conclusion, Hep-1 and Hep-2 peptide responses in experimental mouse agree with the known biology of hepcidin mRNA regulators, and their measurement can now be implemented in experimental mouse models to provide novel insights in post-transcriptional regulation, hepcidin function, and kinetics. PMID:21408141

  12. Animal models of bronchopulmonary dysplasia. The term mouse models

    Science.gov (United States)

    Berger, Jessica

    2014-01-01

    The etiology of bronchopulmonary dysplasia (BPD) is multifactorial, with genetics, ante- and postnatal sepsis, invasive mechanical ventilation, and exposure to hyperoxia being well described as contributing factors. Much of what is known about the pathogenesis of BPD is derived from animal models being exposed to the environmental factors noted above. This review will briefly cover the various mouse models of BPD, focusing mainly on the hyperoxia-induced lung injury models. We will also include hypoxia, hypoxia/hyperoxia, inflammation-induced, and transgenic models in room air. Attention to the stage of lung development at the timing of the initiation of the environmental insult and the duration of lung injury is critical to attempt to mimic the human disease pulmonary phenotype, both in the short term and in outcomes extending into childhood, adolescence, and adulthood. The various indexes of alveolar and vascular development as well as pulmonary function including pulmonary hypertension will be highlighted. The advantages (and limitations) of using such approaches will be discussed in the context of understanding the pathogenesis of and targeting therapeutic interventions to ameliorate human BPD. PMID:25305249

  13. Mouse models for Down syndrome-associated developmental cognitive disabilities.

    Science.gov (United States)

    Liu, Chunhong; Belichenko, Pavel V; Zhang, Li; Fu, Dawei; Kleschevnikov, Alexander M; Baldini, Antonio; Antonarakis, Stylianos E; Mobley, William C; Yu, Y Eugene

    2011-01-01

    Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes. Copyright © 2011 S. Karger AG, Basel.

  14. [Genetically engineered mice: mouse models for cancer research].

    Science.gov (United States)

    Szymańska, Hanna

    2007-10-26

    Genetically engineered mice (GEM) have been extensively used to model human cancer. Mouse models mimic the morphology, histopathology, phenotype, and genotype of the corresponding cancer in humans. GEM mice are created by random integration of a transgene into the genome, which results in gene overexpression (transgenic mice); gene deletion (knock-out mice); or targeted insertion of the transgene in a selected locus (knock-in mice). Knock-out may be constitutive, i.e. total inactivation of the gene of interest in any cell, or conditional, i.e. tissue-specific inactivation of the gene. Gene knock-down (RNAi) and humanization of the mouse are more sophisticated models of GEM mice. RNA interference (RNAi) is a mechanism in which double-stranded RNAs inhibits the respective gene expression by inducing degradation of its mRNA. Humanization is based on replacing a mouse gene by its human counterpart. The alterations in genes in GEM have to be heritable. The opportunities provided by employing GEM cancer models are: analysis of the role of specific cancer genes and modifier genes, evaluation of conventional cancer therapies and new drugs, identification of cancer markers of tumor growth, analysis of the influence of the tumor's microenvironment on tumor formation, and the definition of the pre-clinical, discrete steps of tumorigenesis. The validation of mouse models of human cancer is the task of the MMHCC (Mouse Models of Human Cancer Consortium). The GEM models of breast, pancreatic, intestinal and colon, and prostate cancer are the most actively explored. In contrast, the models of brain tumors and ovary, cervical, and skin cancer are in the early stage of investigation.

  15. Towards a mouse model of depression : a psychoneuroendocrine approach

    NARCIS (Netherlands)

    Dalm, Sergiu

    2012-01-01

    Chronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new drugs are urgently needed. The objective of the research was to develop a mouse model of depression that

  16. Rapid genetic algorithm optimization of a mouse computational model: benefits for anthropomorphization of neonatal mouse cardiomyocytes.

    Science.gov (United States)

    Bot, Corina T; Kherlopian, Armen R; Ortega, Francis A; Christini, David J; Krogh-Madsen, Trine

    2012-01-01

    While the mouse presents an invaluable experimental model organism in biology, its usefulness in cardiac arrhythmia research is limited in some aspects due to major electrophysiological differences between murine and human action potentials (APs). As previously described, these species-specific traits can be partly overcome by application of a cell-type transforming clamp (CTC) to anthropomorphize the murine cardiac AP. CTC is a hybrid experimental-computational dynamic clamp technique, in which a computationally calculated time-dependent current is inserted into a cell in real-time, to compensate for the differences between sarcolemmal currents of that cell (e.g., murine) and the desired species (e.g., human). For effective CTC performance, mismatch between the measured cell and a mathematical model used to mimic the measured AP must be minimal. We have developed a genetic algorithm (GA) approach that rapidly tunes a mathematical model to reproduce the AP of the murine cardiac myocyte under study. Compared to a prior implementation that used a template-based model selection approach, we show that GA optimization to a cell-specific model results in a much better recapitulation of the desired AP morphology with CTC. This improvement was more pronounced when anthropomorphizing neonatal mouse cardiomyocytes to human-like APs than to guinea pig APs. CTC may be useful for a wide range of applications, from screening effects of pharmaceutical compounds on ion channel activity, to exploring variations in the mouse or human genome. Rapid GA optimization of a cell-specific mathematical model improves CTC performance and may therefore expand the applicability and usage of the CTC technique.

  17. Modeling fragile X syndrome in the Fmr1 knockout mouse

    Science.gov (United States)

    Kazdoba, Tatiana M.; Leach, Prescott T.; Silverman, Jill L.; Crawley, Jacqueline N.

    2014-01-01

    Summary Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS. PMID:25606362

  18. A fully humanized transgenic mouse model of Huntington disease.

    Science.gov (United States)

    Southwell, Amber L; Warby, Simon C; Carroll, Jeffrey B; Doty, Crystal N; Skotte, Niels H; Zhang, Weining; Villanueva, Erika B; Kovalik, Vlad; Xie, Yuanyun; Pouladi, Mahmoud A; Collins, Jennifer A; Yang, X William; Franciosi, Sonia; Hayden, Michael R

    2013-01-01

    Silencing the mutant huntingtin gene (muHTT) is a direct and simple therapeutic strategy for the treatment of Huntington disease (HD) in principle. However, targeting the HD mutation presents challenges because it is an expansion of a common genetic element (a CAG tract) that is found throughout the genome. Moreover, the HTT protein is important for neuronal health throughout life, and silencing strategies that also reduce the wild-type HTT allele may not be well tolerated during the long-term treatment of HD. Several HTT silencing strategies are in development that target genetic sites in HTT that are outside of the CAG expansion, including HD mutation-linked single-nucleotide polymorphisms and the HTT promoter. Preclinical testing of these genetic therapies has required the development of a new mouse model of HD that carries these human-specific genetic targets. To generate a fully humanized mouse model of HD, we have cross-bred BACHD and YAC18 on the Hdh(-/-) background. The resulting line, Hu97/18, is the first murine model of HD that fully genetically recapitulates human HD having two human HTT genes, no mouse Hdh genes and heterozygosity of the HD mutation. We find that Hu97/18 mice display many of the behavioral changes associated with HD including motor, psychiatric and cognitive deficits, as well as canonical neuropathological abnormalities. This mouse line will be useful for gaining additional insights into the disease mechanisms of HD as well as for testing genetic therapies targeting human HTT.

  19. Humanized chimeric mouse models of hepatitis B virus infection

    Directory of Open Access Journals (Sweden)

    Suwan Sun

    2017-06-01

    Full Text Available Hepatitis B virus (HBV infection is associated with an increased risk of hepatic cirrhosis, hepatocellular carcinoma, fulminant hepatitis and end-stage hepatic failure. Despite the availability of anti-HBV therapies, HBV infection remains a major global public health problem. Developing an ideal animal model of HBV infection to clarify the details of the HBV replication process, the viral life cycle, the resulting immunoresponse and the precise pathogenesis of HBV is difficult because HBV has an extremely narrow host range and almost exclusively infects humans. In this review, we summarize and evaluate animal models available for studying HBV infection, especially focusing on humanized chimeric mouse models, and we discuss future development trends regarding immunocompetent humanized mouse models that can delineate the natural history and immunopathophysiology of HBV infection.

  20. A STAT-1 Knockout Mouse Model for Machupo Virus Pathogenesis

    Science.gov (United States)

    2011-06-14

    Machupo virus (strain Carvallo) which had been passaged 3-4 times in suckling hamster brain and subsequently twice in Vero cell culture. For...values for clinical chemistry parameters across various species of animal models , as well as human infections, is needed. Total white blood cell ...available soon. A STAT-1 knockout mouse model for Machupo virus pathogenesis Virology Journal 2011, 8:300 doi:10.1186/1743-422X-8-300 Steven B Bradfute

  1. Uterine disorders and pregnancy complications: insights from mouse models

    OpenAIRE

    Lim, Hyunjung Jade; Wang, Haibin

    2010-01-01

    Much of our knowledge of human uterine physiology and pathology has been extrapolated from the study of diverse animal models, as there is no ideal system for studying human uterine biology in vitro. Although it remains debatable whether mouse models are the most suitable system for investigating human uterine function(s), gene-manipulated mice are considered by many the most useful tool for mechanistic analysis, and numerous studies have identified many similarities in female reproduction be...

  2. Practical use of advanced mouse models for lung cancer.

    Science.gov (United States)

    Safari, Roghaiyeh; Meuwissen, Ralph

    2015-01-01

    To date a variety of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) mouse models have been developed that mimic human lung cancer. Chemically induced or spontaneous lung cancer in susceptible inbred strains has been widely used, but the more recent genetically engineered somatic mouse models recapitulate much better the genotype-phenotype correlations found in human lung cancer. Additionally, improved orthotopic transplantation of primary human cancer tissue fragments or cells into lungs of immune-compromised mice can be valuable tools for preclinical research such as antitumor drug tests. Here we give a short overview of most somatic mouse models for lung cancer that are currently in use. We accompany each different model with a description of its practical use and application for all major lung tumor types, as well as the intratracheal injection or direct injection of fresh or freeze-thawed tumor cells or tumor cell lines into lung parenchyma of recipient mice. All here presented somatic mouse models are based on the ability to (in) activate specific alleles at a time, and in a tissue-specific cell type, of choice. This spatial-temporal controlled induction of genetic lesions allows the selective introduction of main genetic lesions in an adult mouse lung as found in human lung cancer. The resulting conditional somatic mouse models can be used as versatile powerful tools in basic lung cancer research and preclinical translational studies alike. These distinctively advanced lung cancer models permit us to investigate initiation (cell of origin) and progression of lung cancer, along with response and resistance to drug therapy. Cre/lox or FLP/frt recombinase-mediated methods are now well-used techniques to develop tissue-restricted lung cancer in mice with tumor-suppressor gene and/or oncogene (in)activation. Intranasal or intratracheal administration of engineered adenovirus-Cre or lentivirus-Cre has been optimized for introducing Cre

  3. Humanized mouse models for HIV-1 infection of the CNS.

    Science.gov (United States)

    Honeycutt, Jenna B; Sheridan, Patricia A; Matsushima, Glenn K; Garcia, J Victor

    2015-06-01

    Since the onset of the HIV epidemic, there has been a shift from a deadly diagnosis to the management of a chronic disease. This shift is the result of the development of highly effective drugs that are able to suppress viral replication for years. The availability of these regimens has also shifted the neurocognitive pathology associated with infection from potentially devastating to a much milder phenotype. As the disease outcome has changed significantly with the availability of antiretroviral therapy, there is an opportunity to re-evaluate the currently available models to address the neurocognitive pathology seen in suppressed patients. In the following, we seek to summarize the current literature on humanized mouse models and their utility in understanding how HIV infection leads to changes in the central nervous system (CNS). Also, we identify some of the unanswered questions regarding HIV infection of the CNS as well as the opportunities and limitations of currently existing models to address those questions. Finally, our conclusions indicate that the earlier humanized models used to study HIV infection in the CNS provided an excellent foundation for the type of work currently being performed using novel humanized mouse models. We also indicate the potential of some humanized mouse models that have not been used as of this time for the analysis of HIV infection in the brain.

  4. Mouse-based genetic modeling and analysis of Down syndrome

    Science.gov (United States)

    Xing, Zhuo; Li, Yichen; Pao, Annie; Bennett, Abigail S.; Tycko, Benjamin; Mobley, William C.; Yu, Y. Eugene

    2016-01-01

    Introduction Down syndrome (DS), caused by human trisomy 21 (Ts21), can be considered as a prototypical model for understanding the effects of chromosomal aneuploidies in other diseases. Human chromosome 21 (Hsa21) is syntenically conserved with three regions in the mouse genome. Sources of data A review of recent advances in genetic modeling and analysis of DS. Using Cre/loxP-mediated chromosome engineering, a substantial number of new mouse models of DS have recently been generated, which facilitates better understanding of disease mechanisms in DS. Areas of agreement Based on evolutionary conservation, Ts21 can be modeled by engineered triplication of Hsa21 syntenic regions in mice. The validity of the models is supported by the exhibition of DS-related phenotypes. Areas of controversy Although substantial progress has been made, it remains a challenge to unravel the relative importance of specific candidate genes and molecular mechanisms underlying the various clinical phenotypes. Growing points Further understanding of mechanisms based on data from mouse models, in parallel with human studies, may lead to novel therapies for clinical manifestations of Ts21 and insights to the roles of aneuploidies in other developmental disorders and cancers. PMID:27789459

  5. Chemically induced mouse models of intestinal inflammation.

    Science.gov (United States)

    Wirtz, Stefan; Neufert, Clemens; Weigmann, Benno; Neurath, Markus F

    2007-01-01

    Animal models of intestinal inflammation are indispensable for our understanding of the pathogenesis of Crohn disease and ulcerative colitis, the two major forms of inflammatory bowel disease in humans. Here, we provide protocols for establishing murine 2,4,6-trinitro benzene sulfonic acid (TNBS)-, oxazolone- and both acute and chronic dextran sodium sulfate (DSS) colitis, the most widely used chemically induced models of intestinal inflammation. In the former two models, colitis is induced by intrarectal administration of the covalently reactive reagents TNBS/oxazolone, which are believed to induce a T-cell-mediated response against hapten-modified autologous proteins/luminal antigens. In the DSS model, mice are subjected several days to drinking water supplemented with DSS, which seems to be directly toxic to colonic epithelial cells of the basal crypts. The procedures for the hapten models of colitis and acute DSS colitis can be accomplished in about 2 weeks but the protocol for chronic DSS colitis takes about 2 months.

  6. Mouse models of myeloproliferative neoplasms: JAK of all grades

    Directory of Open Access Journals (Sweden)

    Juan Li

    2011-05-01

    Full Text Available In 2005, several groups identified a single gain-of-function point mutation in the JAK2 kinase that was present in the majority of patients with myeloproliferative neoplasms (MPNs. Since this discovery, much effort has been dedicated to understanding the molecular consequences of the JAK2V617F mutation in the haematopoietic system. Three waves of mouse models have been produced recently (bone marrow transplantation, transgenic and targeted knock-in, which have facilitated the understanding of the molecular pathogenesis of JAK2V617F-positive MPNs, providing potential platforms for designing and validating novel therapies in humans. This Commentary briefly summarises the first two types of mouse models and then focuses on the more recently generated knock-in models.

  7. Mouse models of ciliopathies: the state of the art

    Directory of Open Access Journals (Sweden)

    Dominic P. Norris

    2012-05-01

    Full Text Available The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such as Meckel-Grüber syndrome (MKS, Joubert syndrome (JBTS, Bardet-Biedl syndrome (BBS and Alström syndrome (ALS. Reflecting the manifold requirements for cilia in signalling, sensation and motility, different ciliopathies exhibit common elements. The mouse has been used widely as a model organism for the study of ciliopathies. Although many mutant alleles have proved lethal, continued investigations have led to the development of better models. Here, we review current mouse models of a core set of ciliopathies, their utility and future prospects.

  8. Transgenic mouse models of metabolic bone disease.

    Science.gov (United States)

    McCauley, L K

    2001-07-01

    The approach of gene-targeted animal models is likely the most important experimental tool contributing to recent advances in skeletal biology. Modifying the expression of a gene in vivo, and the analysis of the consequences of the mutation, are central to the understanding of gene function during development and physiology, and therefore to our understanding of the gene's role in disease states. Researchers had been limited to animal models primarily involving pharmaceutical manipulations and spontaneous mutations. With the advent of gene targeting, however, animal models that impact our understanding of metabolic bone disease have evolved dramatically. Interestingly, some genes that were expected to yield dramatic phenotypes in bone, such as estrogen receptor-alpha or osteopontin, proved to have subtle phenotypes, whereas other genes, such as interleukin-5 or osteoprotegerin, were initially identified as having a role in bone metabolism via the analysis of their phenotype after gene ablation or overexpression. Particularly important has been the advance in knowledge of osteoblast and osteoclast independent and dependent roles via the selective targeting of genes and the consequent disruption of bone formation, bone resorption, or both. Our understanding of interactions of the skeletal system with other systems, ie, the vascular system and homeostatic controls of adipogenesis, has evolved via animal models such as the matrix gla protein, knock-out, and the targeted overexpression of Delta FosB. Challenging transgenic models such as the osteopontin-deficient mice with mediators of bone remodeling like parathyroid hormone and mechanical stimuli and extending phenotype characterization to mechanistic in vitro studies of primary bone cells is providing additional insight into the mechanisms involved in pathologic states and their potentials for therapeutic strategies. This review segregates characterization of transgenic models based on the category of gene altered

  9. A transgenic mouse model for trilateral retinoblastoma

    NARCIS (Netherlands)

    O'Brien, J.M.; Marcus, D.M.; Bernards, R.A.; Carpenter, J.L.; Windle, J.J.; Mellon, P.; Albert, D.M.

    1990-01-01

    We present a murine model of trilateral retinoblastoma. Ocular retinoblastoma and central nervous system tumors are observed in a line of mice formed by the transgenic expression of SV40 T-antigen. An oncogenic protein known to bind to the retinoblastoma gene product (p105-Rb) is specifically

  10. Decerebrate mouse model for studies of the spinal cord circuits.

    Science.gov (United States)

    Meehan, Claire F; Mayr, Kyle A; Manuel, Marin; Nakanishi, Stan T; Whelan, Patrick J

    2017-04-01

    The adult decerebrate mouse model (a mouse with the cerebrum removed) enables the study of sensory-motor integration and motor output from the spinal cord for several hours without compromising these functions with anesthesia. For example, the decerebrate mouse is ideal for examining locomotor behavior using intracellular recording approaches, which would not be possible using current anesthetized preparations. This protocol describes the steps required to achieve a low-blood-loss decerebration in the mouse and approaches for recording signals from spinal cord neurons with a focus on motoneurons. The protocol also describes an example application for the protocol: the evocation of spontaneous and actively driven stepping, including optimization of these behaviors in decerebrate mice. The time taken to prepare the animal and perform a decerebration takes ∼2 h, and the mice are viable for up to 3-8 h, which is ample time to perform most short-term procedures. These protocols can be modified for those interested in cardiovascular or respiratory function in addition to motor function and can be performed by trainees with some previous experience in animal surgery.

  11. A Progressive Translational Mouse Model of Human VCP Disease: The VCP R155H/+ Mouse

    Science.gov (United States)

    Nalbandian, Angèle; Llewellyn, Katrina J.; Badadani, Mallikarjun; Yin, Hong Z.; Nguyen, Christopher; Katheria, Veeral; Watts, Giles; Mukherjee, Jogeshwar; Vesa, Jouni; Caiozzo, Vincent; Mozaffar, Tahseen; Weiss, John H.; Kimonis, Virginia E.

    2012-01-01

    Introduction Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion Body Myopathy (hIBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently they have been linked to 2% of familial ALS cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis. Methods The VCPR155H/+ knock-in mouse model was assessed for muscle strength, immunohistochemical, Western, apoptosis, autophagy and MicroPET/CT imaging analyses. Results VCPR155H/+ mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons. Discussion VCPR155H/+ knock-in mice represent an excellent pre-clinical model for understanding VCP-associated disease mechanisms and future treatments. PMID:23169451

  12. An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis.

    Science.gov (United States)

    Paschall, Amy V; Liu, Kebin

    2016-08-14

    Metastasis is the primary cause of mortality of breast cancer patients. The mechanism underlying cancer cell metastasis, including breast cancer metastasis, is largely unknown and is a focus in cancer research. Various breast cancer spontaneous metastasis mouse models have been established. Here, we report a simplified procedure to establish orthotopic transplanted breast cancer primary tumor and resultant spontaneous metastasis that mimic human breast cancer metastasis. Combined with the bioluminescence live tumor imaging, this mouse model allows tumor growth and progression kinetics to be monitored and quantified. In this model, a low dose (1 x 10(4) cells) of 4T1-Luc breast cancer cells was injected into BALB/c mouse mammary fat pad using a tuberculin syringe. Mice were injected with luciferin and imaged at various time points using a bioluminescent imaging system. When the primary tumors grew to the size limit as in the IACUC-approved protocol (approximately 30 days), mice were anesthetized under constant flow of 2% isoflurane and oxygen. The tumor area was sterilized with 70% ethanol. The mouse skin around the tumor was excised to expose the tumor which was removed with a pair of sterile scissors. Removal of the primary tumor extends the survival of the 4T-1 tumor-bearing mice for one month. The mice were then repeatedly imaged for metastatic tumor spreading to distant organs. Therapeutic agents can be administered to suppress tumor metastasis at this point. This model is simple and yet sensitive in quantifying breast cancer cell growth in the primary site and progression kinetics to distant organs, and thus is an excellent model for studying breast cancer growth and progression, and for testing anti-metastasis therapeutic and immunotherapeutic agents in vivo.

  13. Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap.

    Science.gov (United States)

    Morton, J Jason; Bird, Gregory; Refaeli, Yosef; Jimeno, Antonio

    2016-11-01

    Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highly immunodeficient mouse strains into which human immune systems can be engrafted can help bridge this gap. Humanized mice (HM) allow researchers to examine xenograft growth in the context of a human immune system and resultant tumor microenvironment, and recent studies have highlighted the increased similarities in attendant tumor structure, metastasis, and signaling to those features in cancer patients. This setting also facilitates the examination of investigational cancer therapies, including new immunotherapies. This review discusses recent advancements in the generation and application of HM models, their promise in cancer research, and their potential in generating clinically relevant treatments. This review also focuses on current efforts to improve HM models by engineering mouse strains expressing human cytokines or HLA proteins and implanting human bone, liver, and thymus tissue to facilitate immune cell maturation and trafficking. Finally, we discuss how these improvements may help direct future HM model cancer studies. Cancer Res; 76(21); 6153-8. ©2016 AACR. ©2016 American Association for Cancer Research.

  14. A consensus definition of cataplexy in mouse models of narcolepsy.

    Science.gov (United States)

    Scammell, Thomas E; Willie, Jon T; Guilleminault, Christian; Siegel, Jerome M

    2009-01-01

    People with narcolepsy often have episodes of cataplexy, brief periods of muscle weakness triggered by strong emotions. Many researchers are now studying mouse models of narcolepsy, but definitions of cataplexy-like behavior in mice differ across labs. To establish a common language, the International Working Group on Rodent Models of Narcolepsy reviewed the literature on cataplexy in people with narcolepsy and in dog and mouse models of narcolepsy and then developed a consensus definition of murine cataplexy. The group concluded that murine cataplexy is an abrupt episode of nuchal atonia lasting at least 10 seconds. In addition, theta activity dominates the EEG during the episode, and video recordings document immobility. To distinguish a cataplexy episode from REM sleep after a brief awakening, at least 40 seconds of wakefulness must precede the episode. Bouts of cataplexy fitting this definition are common in mice with disrupted orexin/hypocretin signaling, but these events almost never occur in wild type mice. It remains unclear whether murine cataplexy is triggered by strong emotions or whether mice remain conscious during the episodes as in people with narcolepsy. This working definition provides helpful insights into murine cataplexy and should allow objective and accurate comparisons of cataplexy in future studies using mouse models of narcolepsy.

  15. Nonspecific airway reactivity in a mouse model of asthma

    Energy Technology Data Exchange (ETDEWEB)

    Collie, D.D.; Wilder, J.A.; Bice, D.E.

    1995-12-01

    Animal models are indispensable for studies requiring an intact immune system, especially for studying the pathogenic mechanisms in atopic diseases, regulation of IgE production, and related biologic effects. Mice are particularly suitable and have been used extensively for such studies because their immune system is well characterized. Further, large numbers of mutants or inbred strains of mice are available that express deficiencies of individual immunologic processes, inflammatory cells, or mediator systems. By comparing reactions in such mice with appropriate control animals, the unique roles of individual cells or mediators may be characterized more precisely in the pathogenesis of atopic respiratory diseases including asthma. However, given that asthma in humans is characterized by the presence of airway hyperresponsiveness to specific and nonspecific stimuli, it is important that animal models of this disease exhibit similar physiologic abnormalities. In the past, the size of the mouse has limited its versatility in this regard. However, recent studies indicate the feasibility of measuring pulmonary responses in living mice, thus facilitating the physiologic evaluation of putative mouse models of human asthma that have been well charcterized at the immunologic and patholigic level. Future work will provide details of the morphometry of the methacholine-induced bronchoconstriction and will further seek to determine the relationship between cigarette smoke exposure and the development of NS-AHR in the transgenic mouse model.

  16. [Establishment and evaluation of experimental sepsis mouse model].

    Science.gov (United States)

    Wang, Li-Yan; Xu, Ruo-Nan; Han, Gen-Cheng; Wang, Ren-Xi; Chen, Guo-Jiang; Xiao, He; Hou, Chun-Mei; Shen, Bei-Fen; Li, Yan

    2010-06-01

    After treating with chemotherapy or immunosuppressant, malignant diseases of hematopoietic system such as leukemia, malignant lymphoma and aplastic anemia usually induced severe infection such as sepsis. Sepsis which is hard to be diagnosed causes high death rate. This study was purposed to establish an experimental sepsis mouse model so as to provide a basis for pathogenesis and intervention study. A classic caecal ligation and puncture (CLP) was used to establish experimental sepsis model. ELISA was used to detect levels of C5a, IL-6, TNFalpha, and IFN-gamma. Flow Cytometry was applied to measure apoptosis of lymphocytes in thymus and mesentery. The pathologic changes of thymus and spleen were confirmed by HE staining. The results showed that almost 70%-80% mice died at 72 hours after CLP. Only approximate 20% animal survived during finite time, mice in CLP group had significant weight lose. Meanwhile large release of different inflammatory mediators which are related with sepsis (C5a, IL-6, TNF-alpha, and IFN-gamma) was observed after CLP. Apoptosis of lymphocytes in thymus and mesentery lymphonodus was enhanced markedly after CLP. Significantly pathologic injury was also observed in thymus and spleen. It is concluded that a mouse model of experimental sepsis was successfully established by caecal ligation and puncture which can well mimic the clinical symptom of sepsis. The experimental sepsis mouse model provides an excellent tool for exploring the pathogenesis and intervention ways for sepsis accompanied with complicated malignant hematological diseases in vivo.

  17. Magnolol inhibits the inflammatory response in mouse mammary epithelial cells and a mouse mastitis model.

    Science.gov (United States)

    Wei, Wang; Dejie, Liang; Xiaojing, Song; Tiancheng, Wang; Yongguo, Cao; Zhengtao, Yang; Naisheng, Zhang

    2015-02-01

    Mastitis comprises an inflammation of the mammary gland, which is almost always linked with bacterial infection. The treatment of mastitis concerns antimicrobial substances, but not very successful. On the other hand, anti-inflammatory therapy with Chinese traditional medicine becomes an effective way for treating mastitis. Magnolol is a polyphenolic binaphthalene compound extracted from the stem bark of Magnolia sp., which has been shown to exert a potential for anti-inflammatory activity. The purpose of this study was to investigate the protective effects of magnolol on inflammation in lipopolysaccharide (LPS)-induced mastitis mouse model in vivo and the mechanism of this protective effects in LPS-stimulated mouse mammary epithelial cells (MMECs) in vitro. The damage of tissues was determined by histopathology and myeloperoxidase (MPO) assay. The expression of pro-inflammatory cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and Toll-like receptor 4 (TLR4) were determined by Western blot. The results showed that magnolol significantly inhibit the LPS-induced TNF-α, IL-6, and IL-1β production both in vivo and vitro. Magnolol declined the phosphorylation of IκBα, p65, p38, ERK, and JNK in LPS-stimulated MMECs. Furthermore, magnolol inhibited the expression of TLR4 in LPS-stimulated MMECs. In vivo study, it was also observed that magnolol attenuated the damage of mastitis tissues in the mouse models. These findings demonstrated that magnolol attenuate LPS-stimulated inflammatory response by suppressing TLR4/NF-κB/mitogen-activated protein kinase (MAPK) signaling system. Thereby, magnolol may be a therapeutic agent against mastitis.

  18. A transgenic mouse model for trilateral retinoblastoma.

    Science.gov (United States)

    O'Brien, J M; Marcus, D M; Bernards, R; Carpenter, J L; Windle, J J; Mellon, P; Albert, D M

    1990-08-01

    We present a murine model of trilateral retinoblastoma. Ocular retinoblastoma and central nervous system tumors are observed in a line of mice formed by the transgenic expression of SV40 T-antigen. An oncogenic protein known to bind to the retinoblastoma gene product (p105-Rb) is specifically expressed within retinal cells in this model. All animals that carry this genetic alteration develop multifocal retinal tumors. Midbrain tumors are observed in 15% of ocular tumor-bearing animals, and these arise ventral to the cerebral aqueduct at the level of the pineal gland. Both ocular and central nervous system neoplasms are heritable in heterozygous offspring through 10 sequential generations of breeding. Retinal tumors display the gross appearance, invasive properties, light and electron microscopic features, and immunohistochemical staining characteristics of human retinoblastoma. The light and electron microscopic characteristics as well as immunocytochemical features of undifferentiated midline central nervous system neoplasms further correlate with human trilateral retinoblastoma. We postulate an alternative mechanism of retinoblastoma tumorigenesis that involves functional inactivation of retinoblastoma protein locally in the face of an intact retinoblastoma gene locus.

  19. Long-term Neuroglial Cocultures as a Brain Aging Model: Hallmarks of Senescence, MicroRNA Expression Profiles, and Comparison With In Vivo Models.

    Science.gov (United States)

    Bigagli, Elisabetta; Luceri, Cristina; Scartabelli, Tania; Dolara, Piero; Casamenti, Fiorella; Pellegrini-Giampietro, Domenico E; Giovannelli, Lisa

    2016-01-01

    Our purpose was to evaluate long-term neuroglial cocultures as a model for investigating senescence in the nervous system and to assess its similarities with in vivo models. To this aim, we maintained the cultures from 15 days in vitro (mature cultures) up to 27 days in vitro (senescent cultures), measuring senescence-associated, neuronal, dendritic, and astrocytic markers. Whole microRNA expression profiles were compared with those measured in the cortex of 18- and 24-month-old C57Bl/6J aged mice and of transgenic TgCRND8 mice, a model of amyloid-β deposition. Neuroglial cocultures displayed features of cellular senescence (increased senescence-associated-β-galactosidase activity, oxidative stress, γ-H2AX expression, IL-6 production, astrogliosis) that were concentration dependently counteracted by the antiaging compound resveratrol (1-5 µM). Among the 1,080 microRNAs analyzed, 335 were downregulated or absent in 27 compared with 15 days in vitro and resveratrol reversed this effect. A substantial overlapping was found between age-associated changes in microRNA expression profiles in vitro and in TgCRND8 mice but not in physiologically aged mice, indicating that this culture model displays more similarities with pathological than physiological brain aging. Our results demonstrate that neuroglial cocultures aged in vitro can be useful for investigating the cellular and molecular mechanisms of brain aging and for preliminary testing of protective compounds. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Establishing the colitis-associated cancer progression mouse models.

    Science.gov (United States)

    Zheng, Haiming; Lu, Zhanjun; Wang, Ruhua; Chen, Niwei; Zheng, Ping

    2016-12-01

    Inflammatory bowel disease (IBD) has been reported as an important inducer of colorectal cancer (CRC). The most malignant IBD-associated CRC type has been highlighted as colitis-associated cancer (CAC). However, lack of CAC cases and difficulties of the long follow-up research have challenged researchers in molecular mechanism probing. Here, we established pre-CAC mouse models (dextran sulfate sodium [DSS] group and azoxymethane [AOM] group) and CAC mouse model (DSS/AOM group) to mimic human CAC development through singly or combinational treatment with DSS and AOM followed by disease activity index analysis. We found that these CAC mice showed much more severe disease phenotype, including serious diarrhea, body weight loss, rectal prolapse and bleeding, bloody stool, tumor burden, and bad survival. By detecting expression patterns of several therapeutic targets-Apc, p53, Kras, and TNF-α-in these mouse models through western blot, histology analysis, qRT-PCR, and ELISA methods, we found that the oncogene Kras expression remained unchanged, while the tumor suppressors-Apc and p53 expression were both significantly downregulated with malignancy progression from pre-CAC to CAC, and TNF-α level was elevated the most in CAC mice blood which is of potential clinical use. These data indicated the successful establishment of CAC development mouse models, which mimics human CAC well both in disease phenotype and molecular level, and highlighted the promoting role of inflammation in CAC progression. This useful tool will facilitate the further study in CAC molecular mechanism. © The Author(s) 2016.

  1. Spontaneous rescue from cystic fibrosis in a mouse model

    NARCIS (Netherlands)

    N. Charizopoulou (Nikoletta); M. Wilke (Martina); M. Dorsch (Martina); A.G. Bot (Alice); H. Jorna (Huub); S. Jansen (Silke); F. Stanke (Frauke); H.J. Hedrich; H.R. de Jonge (Hugo); B. Tümmler (Burkhard)

    2006-01-01

    textabstractBackground: From the original CftrTgH(neoim)Hgu mutant mouse model with a divergent genetic background (I29P2, C57BL/6, MFI) we have generated two inbred CftrTgH(neoim)Hgu mutant strains named CF/1 -CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu, which are fertile and show normal growth

  2. Genetically engineered mucin mouse models for inflammation and cancer

    Science.gov (United States)

    Joshi, Suhasini; Kumar, Sushil; Bafna, Sangeeta; Rachagani, Satyanarayana; Wagner, Kay-Uwe; Jain, Maneesh

    2015-01-01

    Mucins are heavily O-glycosylated proteins primarily produced by glandular and ductal epithelial cells, either in membrane-tethered or secretory forms, for providing lubrication and protection from various exogenous and endogenous insults. However, recent studies have linked their aberrant overexpression with infection, inflammation, and cancer that underscores their importance in tissue homeostasis. In this review, we present current status of the existing mouse models that have been developed to gain insights into the functional role(s) of mucins under physiological and pathological conditions. Knockout mouse models for membrane-associated (Muc1 and Muc16) and secretory mucins (Muc2) have helped us to elucidate the role of mucins in providing effective and protective barrier functions against pathological threats, participation in disease progression, and improved our understanding of mucin interaction with biotic and abiotic environmental components. Emphasis is also given to available transgenic mouse models (MUC1 and MUC7), which has been exploited to understand the context-dependent regulation and therapeutic potential of human mucins during inflammation and cancer. PMID:25634251

  3. Mouse models of DNA mismatch repair in cancer research.

    Science.gov (United States)

    Lee, Kyeryoung; Tosti, Elena; Edelmann, Winfried

    2016-02-01

    Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. A genomic analysis of mouse models of breast cancer reveals molecular features of mouse models and relationships to human breast cancer.

    Science.gov (United States)

    Hollern, Daniel P; Andrechek, Eran R

    2014-06-05

    Genomic variability limits the efficacy of breast cancer therapy. To simplify the study of the molecular complexity of breast cancer, researchers have used mouse mammary tumor models. However, the degree to which mouse models model human breast cancer and are reflective of the human heterogeneity has yet to be demonstrated with gene expression studies on a large scale. To this end, we have built a database consisting of 1,172 mouse mammary tumor samples from 26 different major oncogenic mouse mammary tumor models. In this dataset we identified heterogeneity within mouse models and noted a surprising amount of interrelatedness between models, despite differences in the tumor initiating oncogene. Making comparisons between models, we identified differentially expressed genes with alteration correlating with initiating events in each model. Using annotation tools, we identified transcription factors with a high likelihood of activity within these models. Gene signatures predicted activation of major cell signaling pathways in each model, predictions that correlated with previous genetic studies. Finally, we noted relationships between mouse models and human breast cancer at both the level of gene expression and predicted signal pathway activity. Importantly, we identified individual mouse models that recapitulate human breast cancer heterogeneity at the level of gene expression. This work underscores the importance of fully characterizing mouse tumor biology at molecular, histological and genomic levels before a valid comparison to human breast cancer may be drawn and provides an important bioinformatic resource.

  5. Hypersociability in the Angelman syndrome mouse model.

    Science.gov (United States)

    Stoppel, David C; Anderson, Matthew P

    2017-07-01

    Deletions and reciprocal triplications of the human chromosomal 15q11-13 region cause two distinct neurodevelopmental disorders. Maternally-derived deletions or inactivating mutations of UBE3A, a 15q11-13 gene expressed exclusively from the maternal allele in neurons, cause Angelman syndrome, characterized by intellectual disability, motor deficits, seizures, and a characteristic increased social smiling, laughing, and eye contact. Conversely, maternally-derived triplications of 15q11-13 cause a behavioral disorder on the autism spectrum with clinical features that include decreased sociability that we recently reconstituted in mice with Ube3a alone. Based on the unique sociability features reported in Angelman syndrome and the repressed sociability observed when Ube3a gene dosage is increased, we hypothesized that mice with neuronal UBE3A loss that models Angelman syndrome would display evidence of hypersocial behavior. We report that mice with maternally-inherited Ube3a gene deletion (Ube3a mKO ) have a prolonged preference for, and interaction with, social stimuli in the three chamber social approach task. By contrast, interactions with a novel object are reduced. Further, ultrasonic vocalizations and physical contacts are increased in male and female Ube3a mKO mice paired with an unfamiliar genotype-matched female. Single housing wild type mice increased these same social behavior parameters to levels observed in Ube3a mKO mice where this effect was partially occluded. These results indicate sociability is repressed by social experience and the endogenous levels of UBE3A protein and suggest some social behavioral features observed in Angelman syndrome may reflect an increased social motivation. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Mouse model of proximal tubule endocytic dysfunction.

    Science.gov (United States)

    Weyer, Kathrin; Storm, Tina; Shan, Jingdong; Vainio, Seppo; Kozyraki, Renata; Verroust, Pierre J; Christensen, Erik I; Nielsen, Rikke

    2011-11-01

    Several studies have indicated the central role of the megalin/cubilin multiligand endocytic receptor complex in protein reabsorption in the kidney proximal tubule. However, the poor viability of the existing megalin-deficient mice precludes further studies and comparison of homogeneous groups of mice. Megalin- and/or cubilin-deficient mice were generated using a conditional Cre-loxP system, where the Cre gene is driven by the Wnt4 promoter. Kidney tissues from the mice were analysed for megalin and cubilin expression by quantitative reverse transcription-polymerase chain reaction, western blotting and immunohistochemistry. Renal albumin uptake was visualized by immunohistochemistry. Twenty-four-hour urine samples were collected in metabolic cages and analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western blotting. Urinary albumin/creatinine ratios were measured by ELISA and the alkaline picrate method. The Meg(lox/lox);Cre(+), Cubn(lox/lox);Cre(+) and Meg(lox/lox), Cubn(lox/lox);Cre(+) mice were all viable, fertile and developed normal kidneys. Megalin and/or cubilin expression, assessed by immunohistology and western blotting, was reduced by >89%. Consistent with this observation, the mice excreted megalin and cubilin ligands such as transferrin and albumin in addition to low-molecular weight proteins. We further show that megalin/cubilin double-deficient mice excrete albumin with an average of 1.45 ± 0.54 mg/day, suggesting a very low albumin concentration in the glomerular ultrafiltrate. We report here the efficient genetic ablation of megalin, cubilin or both, using a Cre transgene driven by the Wnt4 promoter. The viable megalin/cubilin double-deficient mice now allow for detailed large-scale group analysis, and we anticipate that the mice will be of great value as an animal model for proximal tubulopathies with disrupted endocytosis.

  7. Glycine receptor mouse mutants: model systems for human hyperekplexia.

    Science.gov (United States)

    Schaefer, Natascha; Langlhofer, Georg; Kluck, Christoph J; Villmann, Carmen

    2013-11-01

    Human hyperekplexia is a neuromotor disorder caused by disturbances in inhibitory glycine-mediated neurotransmission. Mutations in genes encoding for glycine receptor subunits or associated proteins, such as GLRA1, GLRB, GPHN and ARHGEF9, have been detected in patients suffering from hyperekplexia. Classical symptoms are exaggerated startle attacks upon unexpected acoustic or tactile stimuli, massive tremor, loss of postural control during startle and apnoea. Usually patients are treated with clonazepam, this helps to dampen the severe symptoms most probably by up-regulating GABAergic responses. However, the mechanism is not completely understood. Similar neuromotor phenotypes have been observed in mouse models that carry glycine receptor mutations. These mouse models serve as excellent tools for analysing the underlying pathomechanisms. Yet, studies in mutant mice looking for postsynaptic compensation of glycinergic dysfunction via an up-regulation in GABAA receptor numbers have failed, as expression levels were similar to those in wild-type mice. However, presynaptic adaptation mechanisms with an unusual switch from mixed GABA/glycinergic to GABAergic presynaptic terminals have been observed. Whether this presynaptic adaptation explains the improvement in symptoms or other compensation mechanisms exist is still under investigation. With the help of spontaneous glycine receptor mouse mutants, knock-in and knock-out studies, it is possible to associate behavioural changes with pharmacological differences in glycinergic inhibition. This review focuses on the structural and functional characteristics of the various mouse models used to elucidate the underlying signal transduction pathways and adaptation processes and describes a novel route that uses gene-therapeutic modulation of mutated receptors to overcome loss of function mutations. © 2013 The British Pharmacological Society.

  8. The EL mouse: a natural model of autism and epilepsy.

    Science.gov (United States)

    Meidenbauer, Joshua J; Mantis, John G; Seyfried, Thomas N

    2011-02-01

    Autism is a multifactorial disorder that involves impairments in social interactions and communication, as well as restricted and repetitive behaviors. About 30% of individuals with autism develop epilepsy by adulthood. The EL mouse has long been studied as a natural model of multifactorial idiopathic generalized epilepsy with complex partial seizures. Because epilepsy is a comorbid trait of autism, we evaluated the EL mouse for behaviors associated with autism. We compared the behavior of EL mice to age-matched control DDY mice, a genetically related nonepileptic strain. The mice were compared in the open field and in the light-dark compartment tests to measure activity, exploratory behavior, and restricted and repetitive behaviors. The social transmission of food preference test was employed to evaluate social communication. Home-cage behavior was also evaluated in EL and DDY mice as a measure of repetitive activity. We found that EL mice displayed several behavioral abnormalities characteristic of autism. Impairments in social interaction and restricted patterns of interest were evident in EL mice. Activity, exploratory behavior, and restricted behavior were significantly greater in EL mice than in DDY mice. EL mice exhibited impairment in the social transmission of food preference assay. In addition, a stereotypic myoclonic jumping behavior was observed in EL mice, but was not seen in DDY mice. It is of interest to note that seizure activity within 24 h of testing exacerbated the autistic behavioral abnormalities found in EL mice. These findings suggest that the EL mouse expresses behavioral abnormalities similar to those seen in persons with autism. We propose that the EL mouse can be utilized as a natural model of autism and epilepsy. Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.

  9. Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

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    Day, Chi-Ping; Merlino, Glenn; Van Dyke, Terry

    2015-01-01

    Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This primer explores the current status, promise and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development. PMID:26406370

  10. Transgenic Mouse Models of Alzheimer Disease: Developing a Better Model as a Tool for Therapeutic Interventions

    Science.gov (United States)

    Kitazawa, Masashi; Medeiros, Rodrigo; LaFerla, Frank M.

    2015-01-01

    Alzheimer disease (AD) is the leading cause of dementia among elderly. Currently, no effective treatment is available for AD. Analysis of transgenic mouse models of AD has facilitated our understanding of disease mechanisms and provided valuable tools for evaluating potential therapeutic strategies. In this review, we will discuss the strengths and weaknesses of current mouse models of AD and the contribution towards understanding the pathological mechanisms and developing effective therapies. PMID:22288400

  11. An Anisotropic Fluid-Solid Model of the Mouse Heart

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    Carson, James P.; Kuprat, Andrew P.; Jiao, Xiangmin; del Pin, Facundo; Einstein, Daniel R.

    2010-01-01

    A critical challenge in biomechanical simulations is the spatial discretization of complex fluid-solid geometries created from imaging. This is especially important when dealing with Lagrangian interfaces, as there must be at a minimum both geometric and topological compatibility between fluid and solid phases, with exact matching of the interfacial nodes being highly desirable. We have developed a solution to this problem and applied the approach to the creation of a 3D fluidsolid mesh of the mouse heart. First, a 50 micron isotropic MRI dataset of a perfusion-fixed mouse heart was segmented into blood, tissue, and background using a customized multimaterial connected fuzzy thresholding algorithm. Then, a multimaterial marching cubes algorithm was applied to produce two compatible isosurfaces, one for the blood-tissue boundary and one for the tissue-background boundary. A multimaterial smoothing algorithm that rigorously conserves volume for each phase simultaneously smoothed the isosurfaces. Next we applied novel automated meshing algorithms to generate anisotropic hybrid meshes with the number of layers and the desired element anisotropy for each material as the only input parameters. As the meshes are scale-invariant within a material and include boundary layer prisms, fluid-structure interaction computations would have a relative error equilibrated over the entire mesh. The resulting model is highly detailed mesh representation of the mouse heart, including features such as chordae and coronary vasculature, that is also maximally efficient to produce the best simulation results for the computational resources available

  12. A mouse kindling model of perimenstrual catamenial epilepsy.

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    Reddy, Doodipala Samba; Gould, Jordan; Gangisetty, O

    2012-06-01

    Catamenial epilepsy is caused by fluctuations in progesterone-derived GABA(A) receptor-modulating anticonvulsant neurosteroids, such as allopregnanolone, that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy by using the neurosteroid-withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (midluteal phase) and increases during their withdrawal (perimenstrual periods) in close association with GABA(A) receptor plasticity. A chronic seizure condition was created by using the hippocampus kindling model in female mice. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Elevated neurosteroid exposure reduced seizure expression in fully kindled mice. Fully kindled mice subjected to neurosteroid withdrawal showed increased generalized seizure frequency and intensity and enhanced seizure susceptibility. They also showed reduced benzodiazepine sensitivity and enhanced neurosteroid potency, similar to the clinical catamenial seizure phenotype. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the α4 and δ subunits of GABA(A) receptors in the hippocampus. These findings demonstrate that endogenous neurosteroids protect against seizure susceptibility and their withdrawal, such as that which occurs during menstruation, leads to exacerbation of seizure activity. This is possibly caused by specific changes in GABA(A) receptor-subunit plasticity and function, therefore providing a novel mouse model of human perimenstrual catamenial epilepsy that can be used for the investigation of disease mechanisms and new therapeutic approaches.

  13. An in vivo mouse model of metastatic human thyroid cancer.

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    Zhang, Lisa; Gaskins, Kelli; Yu, Zhiya; Xiong, Yin; Merino, Maria J; Kebebew, Electron

    2014-04-01

    Mouse models of metastatic human cancers are important tools in preclinical studies for testing new systematic therapies and studying effectors of cancer metastasis. The major drawbacks of current mouse models for metastatic thyroid cancer are that they have low metastasis rates and do not allow in vivo tumor detection. Here, we report and characterize an in vivo detectable metastasis mouse model of human thyroid cancer using multiple thyroid cancer cell lines. Human anaplastic thyroid cancer cell lines 8505C, C-643, SW-1736, and THJ-16T; follicular thyroid cancer cell lines FTC-133, FTC-236, and FTC-238; and Hürthle cell carcinoma cell line XTC-1 were transfected with a linearized pGL4.51[luc2/CMV/Neo] vector or transduced with lentivirus containing Luc2-eGFP reporter genes. The stably transfected cells were injected intravenously into NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. Tumors were detected with an in vivo imaging system-Xenogen IVIS. Vemurafenib, a BRAF inhibitor, was used to treat lung metastases generated from 8505C-Luc2 cells with a BRAF(V600E) mutation to test the accuracy of the model to evaluate response to therapy. Intravenous injection of as few as 30,000 8505C-Luc2 cells produced lung metastases in 100% of the injected mice, and many of these mice also developed bone metastases at a later stage of the disease. Similarly, metastatic tumors also developed in all mice injected with C-643-Luc2, THJ-16T-Luc2, FTC-133-Luc2, FTC-236-Luc2, FTC-238-Luc2, and XTC-1-Luc2 cells. The metastases were easily detectable in vivo, and tumor progression could be dynamically and accurately followed and correlated with the actual tumor burden. Furthermore, disease progression could be easily controlled by adjusting the number of injected cells. The in vivo treatment of 8505C xenograft lung metastases with vemurafenib dramatically reduced the growth and signal intensity with good correlation with actual tumor burden. Herein we report an in vivo detectable mouse model

  14. Mouse models of SCN5A-related cardiac arrhythmias

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    Flavien eCharpentier

    2012-06-01

    Full Text Available Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na+ channel NaV1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, atrial standstill and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This paper reviews some of the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. It also points out that these models also have their own limitations. Overall, mouse models appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodelling of other genes that might participate to the overall phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.

  15. Venous Thrombosis and Cancer: from Mouse Models to Clinical Trials

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    Hisada, Y.; Geddings, J. E.; Ay, C.; Mackman, N.

    2015-01-01

    Cancer patients have a ~4 fold increased risk of venous thromboembolism (VTE) compared with the general population and this is associated with significant morbidity and mortality. This review summarizes our current knowledge of VTE and cancer from mouse models to clinical studies. Notably, risk of VTE varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of VTE than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors and growth factors may directly and indirectly enhance VTE. For example, increased levels of circulating tumor-derived, tissue factor-positive microvesicles may trigger VTE. In a mouse model of ovarian cancer, tumor-derived IL-6 and hepatic thrombopoietin has been linked to increased platelet production and thrombosis. In addition, mouse models of mammary and lung cancer showed that tumor-derived granulocyte colony-stimulating factor causes neutrophilia and activation of neutrophils. Activated neutrophils can release neutrophil extracellular traps (NETs) that enhance thrombosis. Cell-free DNA in the blood derived from cancer cells, NETs and treatment with cytotoxic drugs can activate the clotting cascade. These studies suggest that there are multiple mechanisms for VTE in patients with different types of cancer. Preventing and treating VTE in cancer patients is challenging; the current recommendations are to use low molecular weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent VTE in cancer patients. PMID:25988873

  16. Venous thrombosis and cancer: from mouse models to clinical trials.

    Science.gov (United States)

    Hisada, Y; Geddings, J E; Ay, C; Mackman, N

    2015-08-01

    Cancer patients have a ~4 fold increased risk of venous thromboembolism (VTE) compared with the general population and this is associated with significant morbidity and mortality. This review summarizes our current knowledge of VTE and cancer, from mouse models to clinical studies. Notably, the risk of VTE varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of VTE than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors and growth factors may directly and indirectly enhance VTE. For example, increased levels of circulating tumor-derived, tissue factor-positive microvesicles may trigger VTE. In a mouse model of ovarian cancer, tumor-derived IL-6 and hepatic thrombopoietin have been linked to increased platelet production and thrombosis. In addition, mouse models of mammary and lung cancer showed that tumor-derived granulocyte colony-stimulating factor causes neutrophilia and activation of neutrophils. Activated neutrophils can release neutrophil extracellular traps (NETs) that enhance thrombosis. Cell-free DNA in the blood derived from cancer cells, NETs and treatment with cytotoxic drugs can activate the clotting cascade. These studies suggest that there are multiple mechanisms for VTE in patients with different types of cancer. Preventing and treating VTE in cancer patients is challenging; the current recommendations are to use low-molecular-weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent VTE in cancer patients. © 2015 International Society on Thrombosis and Haemostasis.

  17. [Establishment of a mutant Lumican transgenic mouse model].

    Science.gov (United States)

    Song, Yanzheng; Zhao, Yanyan; Zhang, Fengju; Yu, Yanqiu; Ma, Ling

    2014-01-01

    Pathological myopia (PM) is a hereditary ocular disease leading to severe loss of visual acuity and blindness. Lumican gene (LUM) is one of those candidate genes of PM. The purpose of this study was to establish a mutant Lumican transgenic mouse model, and to prepare for the further study of the pathogenesis of PM. Experimental study. Mutation of LUM gene was created by site-directed mutagenesis. Recombinant DNA techniques were used for the construction of the pRP. EX3d-EF1A>LUM/flag>IRES/hrGFP transgene. The gene fragments were microinjected into the zygote male pronuclei of BDF1 mice, and then the zygote cells alive were transplanted into the oviduct of acceptor pregnant female ICR mice. The F0 generation transgenic mice obtained were named C57-TgN (LUM)CCMU. Genome DNA from mice tail was detected by PCR and Western blotting. Six of 31 F0 generation mice were positive transgenic mice. The western blotting study showed that the flag-tag was expressed in the mouse tail tissue. Sixty-eight of 128 mice (F1 to F3 generation) were positive transgenic mice, the positive rate is 53.13%. The mutant Lumican (cDNA 596T>C) transgenic mouse model has been established. This model will provide fundamental conditions for studies of the pathogenesis of PM. Also it will be the basis of further studies about the effect of Lumican mutation on the development of PM and structure and function of the extra cellular matrix.

  18. Humanized mouse model to study bacterial infections targeting the microvasculature.

    Science.gov (United States)

    Melican, Keira; Aubey, Flore; Duménil, Guillaume

    2014-04-01

    Neisseria meningitidis causes a severe, frequently fatal sepsis when it enters the human blood stream. Infection leads to extensive damage of the blood vessels resulting in vascular leak, the development of purpuric rashes and eventual tissue necrosis. Studying the pathogenesis of this infection was previously limited by the human specificity of the bacteria, which makes in vivo models difficult. In this protocol, we describe a humanized model for this infection in which human skin, containing dermal microvessels, is grafted onto immunocompromised mice. These vessels anastomose with the mouse circulation while maintaining their human characteristics. Once introduced into this model, N. meningitidis adhere exclusively to the human vessels, resulting in extensive vascular damage, inflammation and in some cases the development of purpuric rash. This protocol describes the grafting, infection and evaluation steps of this model in the context of N. meningitidis infection. The technique may be applied to numerous human specific pathogens that infect the blood stream.

  19. Mouse genetic models for temporomandibular joint development and disorders.

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    Suzuki, A; Iwata, J

    2016-01-01

    The temporomandibular joint (TMJ) is a synovial joint essential for hinge and sliding movements of the mammalian jaw. Temporomandibular joint disorders (TMD) are dysregulations of the muscles or the TMJ in structure, function, and physiology, and result in pain, limited mandibular mobility, and TMJ noise and clicking. Although approximately 40-70% adults in the USA have at least one sign of TMD, the etiology of TMD remains largely unknown. Here, we highlight recent advances in our understanding of TMD in mouse models. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

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    Chen Xi

    2011-11-01

    Full Text Available Abstract Background Huntington's disease (HD is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs. Our group has previously demonstrated that calcium (Ca2+ signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128. Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2 and spinocerebellar ataxia 3 (SCA3 mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. Results The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Conclusions Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that Ryan

  1. Mouse Models of Prostate Cancer: Picking the Best Model for the Question

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    Grabowska, Magdalena M.; DeGraff, David J.; Yu, Xiuping; Jin, Ren Jie; Chen, Zhenbang; Borowsky, Alexander D.; Matusik, Robert J.

    2014-01-01

    When the NIH Mouse Models of Human Cancer Consortium (MMCC) initiated the Prostate Steering Committee 15 years ago, there were no genetically engineered mouse (GEM) models of prostate cancer (PCa). Today, a PubMed search for “prostate cancer mouse model” yields 3,200 publications and this list continues to grow. The first generation of GEM utilized the newly discovered and characterized probasin (PB) promoter driving viral oncogenes such as SV40 large T antigen to yield the LADY and TRAMP models. As the PCa research field has matured, the second generation of models has incorporated the single and multiple molecular changes observed in human disease, such as loss of PTEN and over-expression of Myc. Application of these models has revealed that mice are particularly resistant to developing invasive PCa, and once they achieve invasive disease, the PCa rarely resembles human disease. Nevertheless, these models and their application have provided vital information on human PCa progression. The aim of this review is to provide a brief primer on mouse and human prostate histology and pathology, provide descriptions of mouse models, as well as attempt to answer the age old question: Which GEM model of PCa is the best for my research question? PMID:24452759

  2. The calm mouse: an animal model of stress reduction.

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    Gurfein, Blake T; Stamm, Andrew W; Bacchetti, Peter; Dallman, Mary F; Nadkarni, Nachiket A; Milush, Jeffrey M; Touma, Chadi; Palme, Rupert; Di Borgo, Charles Pozzo; Fromentin, Gilles; Lown-Hecht, Rachel; Konsman, Jan Pieter; Acree, Michael; Premenko-Lanier, Mary; Darcel, Nicolas; Hecht, Frederick M; Nixon, Douglas F

    2012-05-09

    Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a "calm mouse model" with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.

  3. A Mouse Model of Hypospadias Induced by Estradiol Benzoate.

    Science.gov (United States)

    He, Hou-Guang; Han, Cong-Hui; Zhang, Wei

    2015-12-01

    We wished to establish a mouse model of hypospadias using injections of estradiol benzoate for investigating the molecular mechanisms of hypospadias. Fifty timed pregnant mice were randomly divided into five study groups: A, B, C, D, and E. These groups were injected subcutaneously with estradiol benzoate mixed with sesame oil at, respectively, the doses of 0, 0.1, 0.5, 2.5, or 12.5 mg kg(-1) days(-1) from gestation day (GD) 12 to GD 16. The pups' mortality was recorded on the day of delivery. Urethras and positions of testes were examined on postnatal day 28. The numbers of live pups were significantly lower in the study groups D and E compared to study group A (p Hypospadias was seen in groups C (3.3 %; 1/30), D (18.2 %; 4/22), and E (21.4 %; 3/14), while cryptorchidism was observed in groups C (10 %; 3/30), D (31.8 %; 7/22), and E (57.1 %; 8/14) on postnatal day 28. The experimental model of hypospadias induced by estradiol benzoate in the group D (2.5 mg kg(-1) days(-1)) was more reliable considering high mortality of the study group E. The dose of estradiol benzoate used in the group D is suitable for establishing mouse model of hypospadias.

  4. Genetic mouse models of brain ageing and Alzheimer's disease.

    Science.gov (United States)

    Bilkei-Gorzo, Andras

    2014-05-01

    Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Experimental Mouse Model of Lumbar Ligamentum Flavum Hypertrophy.

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    Saito, Takeyuki; Yokota, Kazuya; Kobayakawa, Kazu; Hara, Masamitsu; Kubota, Kensuke; Harimaya, Katsumi; Kawaguchi, Kenichi; Hayashida, Mitsumasa; Matsumoto, Yoshihiro; Doi, Toshio; Shiba, Keiichiro; Nakashima, Yasuharu; Okada, Seiji

    2017-01-01

    Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-β1 (TGF-β1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-β1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production.

  6. Genetically Engineered ERα positive breast cancer mouse models

    Science.gov (United States)

    Dabydeen, Sarah A.; Furth, Priscilla A.

    2014-01-01

    The majority of human breast cancers are ER+ but this has proven challenging to model in genetically engineered mice. This review summarizes information on twenty-one mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent. Esr1, Ccdn1, prolactin, TGFα, AIB1, Espl1, and Wnt1 over-expression, Pik3ca gain of function, as well as loss of p53 or loss of Stat1 are associated with ER+ mammary cancer. Treatment with the PPARγ agonist efatutazone in a mouse with Brca1 and p53 deficiency and DMBA exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from three to 26 months and the percentages of cancers that are ER+ vary from 21% to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1 and NIH nude. Most models have only been studied on one strain background. In summary while a range of models is available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization and opportunity for development of new models remains. PMID:24481326

  7. Revisiting the mouse model of oxygen-induced retinopathy

    Directory of Open Access Journals (Sweden)

    Kim CB

    2016-05-01

    Full Text Available Clifford B Kim,1,2 Patricia A D’Amore,2–4 Kip M Connor1,2 1Angiogenesis Laboratory, Massachusetts Eye and Ear, 2Department of Ophthalmology, Harvard Medical School, 3Schepens Eye Research Institute, Massachusetts Eye and Ear, 4Department of Pathology, Harvard Medical School, Boston, MA, USA Abstract: Abnormal blood vessel growth in the retina is a hallmark of many retinal diseases, such as retinopathy of prematurity (ROP, proliferative diabetic retinopathy, and the wet form of age-related macular degeneration. In particular, ROP has been an important health concern for physicians since the advent of routine supplemental oxygen therapy for premature neonates more than 70 years ago. Since then, researchers have explored several animal models to better understand ROP and retinal vascular development. Of these models, the mouse model of oxygen-induced retinopathy (OIR has become the most widely used, and has played a pivotal role in our understanding of retinal angiogenesis and ocular immunology, as well as in the development of groundbreaking therapeutics such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. Numerous refinements to the model have been made since its inception in the 1950s, and technological advancements have expanded the use of the model across multiple scientific fields. In this review, we explore the historical developments that have led to the mouse OIR model utilized today, essential concepts of OIR, limitations of the model, and a representative selection of key findings from OIR, with particular emphasis on current research progress. Keywords: ROP, OIR, angiogenesis

  8. Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics.

    Science.gov (United States)

    Kazdoba, Tatiana M; Leach, Prescott T; Yang, Mu; Silverman, Jill L; Solomon, Marjorie; Crawley, Jacqueline N

    Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism.

  9. A new mouse model to explore therapies for preeclampsia.

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    Abdulwahab Ahmed

    Full Text Available BACKGROUND: Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE. DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF signaling by soluble VEGF receptor 1 (sFlt-1 is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies. CONCLUSIONS/SIGNIFICANCE: We described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.

  10. A mouse model for Meckel syndrome type 3.

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    Cook, Susan A; Collin, Gayle B; Bronson, Roderick T; Naggert, Jürgen K; Liu, Dong P; Akeson, Ellen C; Davisson, Muriel T

    2009-04-01

    Meckel-Gruber syndrome type 3 (MKS3; OMIM 607361) is a severe autosomal recessive disorder characterized by bilateral polycystic kidney disease. Other malformations associated with MKS3 include cystic changes in the liver, polydactyly, and brain abnormalities (occipital encephalocele, hydrocephalus, and Dandy Walker-type cerebellar anomalies). The disorder is hypothesized to be caused by defects in primary cilia. In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium. Here, we describe a spontaneous deletion of the mouse ortholog, Tmem67, which results in polycystic kidney disease and death by 3 wk after birth. Hydrocephalus also occurs in some mutants. We verified the mutated gene by transgenic rescue and characterized the phenotype with microcomputed tomography, histology, scanning electron microscopy, and immunohistochemistry. This mutant provides a mouse model for MKS3 and adds to the growing set of mammalian models essential for studying the role of the primary cilium in kidney function.

  11. Parametric Modeling of the Mouse Left Ventricular Myocardial Fiber Structure.

    Science.gov (United States)

    Merchant, Samer S; Gomez, Arnold David; Morgan, James L; Hsu, Edward W

    2016-09-01

    Magnetic resonance diffusion tensor imaging (DTI) has greatly facilitated detailed quantifications of myocardial structures. However, structural patterns, such as the distinctive transmural rotation of the fibers, remain incompletely described. To investigate the validity and practicality of pattern-based analysis, 3D DTI was performed on 13 fixed mouse hearts and fiber angles in the left ventricle were transformed and fitted to parametric expressions constructed from elementary functions of the prolate spheroidal spatial variables. It was found that, on average, the myocardial fiber helix angle could be represented to 6.5° accuracy by the equivalence of a product of 10th-order polynomials of the radial and longitudinal variables, and 17th-order Fourier series of the circumferential variable. Similarly, the fiber imbrication angle could be described by 10th-order polynomials and 24th-order Fourier series, to 5.6° accuracy. The representations, while relatively concise, did not adversely affect the information commonly derived from DTI datasets including the whole-ventricle mean fiber helix angle transmural span and atlases constructed for the group. The unique ability of parametric models for predicting the 3D myocardial fiber structure from finite number of 2D slices was also demonstrated. These findings strongly support the principle of parametric modeling for characterizing myocardial structures in the mouse and beyond.

  12. Mouse models of cognitive disorders in trisomy 21: a review.

    Science.gov (United States)

    Sérégaza, Zohra; Roubertoux, Pierre L; Jamon, Marc; Soumireu-Mourat, Bernard

    2006-05-01

    Trisomy 21 (TRS21) is the most frequent genetic cause of mental retardation. Although the presence of an extra copy of HSA21 is known to be at the origin of the syndrome, we do not know which 225 HSA21 genes have an effect on cognitive processes. Mouse models of TRS21 have been developed using syntenies between HSA21 and MMU16, MMU10 and MMU17. Available mouse models carry extra fragments of MMU16 or of HSA21 that cover all of HSA21 (chimeric HSA21) or MMU16 (Ts16); some carry large parts of MMU16 (Ts65Dn, Ts1Cje, Ms1Cje), while others have reduced contiguous fragments covering the D21S17-ETS2 region or single transfected genes. This offers a nest design strategy for deciphering cognitive (learning, memory and exploration) and associated brain abnormalities involving each of these chromosomal regions. This review confirms the crucial but not exclusive contribution of the D21S17-ETS2 region encompassing 16 genes to cognitive disorders.

  13. Ghrelin modulates testicular damage in a cryptorchid mouse model

    Science.gov (United States)

    Boekelheide, Kim; Sigman, Mark; Hall, Susan J.; Hwang, Kathleen

    2017-01-01

    Cryptorchidism or undescended testis (UDT) is a common congenital abnormality associated with increased risk for developing male infertility and testicular cancer. This study elucidated the effects of endogenous ghrelin or growth hormone secretagogue receptor (GHSR) deletion on mouse reproductive performance and evaluated the ability of ghrelin to prevent testicular damage in a surgical cryptorchid mouse model. Reciprocal matings with heterozygous/homozygous ghrelin and GHSR knockout mice were performed. Litter size and germ cell apoptosis were recorded and testicular histological evaluations were performed. Wild type and GHSR knockout adult mice were subjected to creation of unilateral surgical cryptorchidism that is a model of heat-induced germ cell death. All mice were randomly separated into two groups: treatment with ghrelin or with saline. To assess testicular damage, the following endpoints were evaluated: testis weight, seminiferous tubule diameter, percentage of seminiferous tubules with spermatids and with multinucleated giant cells. Our findings indicated that endogenous ghrelin deletion altered male fertility. Moreover, ghrelin treatment ameliorated the testicular weight changes caused by surgically induced cryptorchidism. Testicular histopathology revealed a significant preservation of spermatogenesis and seminiferous tubule diameter in the ghrelin-treated cryptorchid testes of GHSR KO mice, suggesting that this protective effect of ghrelin was mediated by an unknown mechanism. In conclusion, ghrelin therapy could be useful to suppress testicular damage induced by hyperthermia, and future investigations will focus on the underlying mechanisms by which ghrelin mitigates testicular damage. PMID:28542403

  14. Development of a Mouse Model of Menopausal Ovarian Cancer

    Science.gov (United States)

    Smith, Elizabeth R.; Wang, Ying; Xu, Xiang-Xi

    2014-01-01

    Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1–5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention. PMID:24616881

  15. Development of A Mouse Model of Menopausal Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Smith

    2014-02-01

    Full Text Available Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; questions of the cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology.A potentially useful model is the germ cell-deficient Wv (white spotting variant mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1-5% (it is not a null mutation. Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer.Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention.

  16. Gait analysis in a mouse model resembling Leigh disease.

    Science.gov (United States)

    de Haas, Ria; Russel, Frans G; Smeitink, Jan A

    2016-01-01

    Leigh disease (LD) is one of the clinical phenotypes of mitochondrial OXPHOS disorders and also known as sub-acute necrotizing encephalomyelopathy. The disease has an incidence of 1 in 77,000 live births. Symptoms typically begin early in life and prognosis for LD patients is poor. Currently, no clinically effective treatments are available. Suitable animal and cellular models are necessary for the understanding of the neuropathology and the development of successful new therapeutic strategies. In this study we used the Ndufs4 knockout (Ndufs4(-/-)) mouse, a model of mitochondrial complex I deficiency. Ndusf4(-/-) mice exhibit progressive neurodegeneration, which closely resemble the human LD phenotype. When dissecting behavioral abnormalities in animal models it is of great importance to apply translational tools that are clinically relevant. To distinguish gait abnormalities in patients, simple walking tests can be assessed, but in animals this is not easy. This study is the first to demonstrate automated CatWalk gait analysis in the Ndufs4(-/-) mouse model. Marked differences were noted between Ndufs4(-/-) and control mice in dynamic, static, coordination and support parameters. Variation of walking speed was significantly increased in Ndufs4(-/-) mice, suggesting hampered and uncoordinated gait. Furthermore, decreased regularity index, increased base of support and changes in support were noted in the Ndufs4(-/-) mice. Here, we report the ability of the CatWalk system to sensitively assess gait abnormalities in Ndufs4(-/-) mice. This objective gait analysis can be of great value for intervention and drug efficacy studies in animal models for mitochondrial disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    Science.gov (United States)

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  18. The German Mouse Clinic: a platform for systemic phenotype analysis of mouse models.

    Science.gov (United States)

    Fuchs, H; Gailus-Durner, V; Adler, T; Pimentel, J A Aguilar; Becker, L; Bolle, I; Brielmeier, M; Calzada-Wack, J; Dalke, C; Ehrhardt, N; Fasnacht, N; Ferwagner, B; Frischmann, U; Hans, W; Hölter, S M; Hölzlwimmer, G; Horsch, M; Javaheri, A; Kallnik, M; Kling, E; Lengger, C; Maier, H; Mossbrugger, I; Mörth, C; Naton, B; Nöth, U; Pasche, B; Prehn, C; Przemeck, G; Puk, O; Racz, I; Rathkolb, B; Rozman, J; Schäble, K; Schreiner, R; Schrewe, A; Sina, C; Steinkamp, R; Thiele, F; Willershäuser, M; Zeh, R; Adamski, J; Busch, D H; Beckers, J; Behrendt, H; Daniel, H; Esposito, I; Favor, J; Graw, J; Heldmaier, G; Höfler, H; Ivandic, B; Katus, H; Klingenspor, M; Klopstock, T; Lengeling, A; Mempel, M; Müller, W; Neschen, S; Ollert, M; Quintanilla-Martinez, L; Rosenstiel, P; Schmidt, J; Schreiber, S; Schughart, K; Schulz, H; Wolf, E; Wurst, W; Zimmer, A; Hrabé de Angelis, M

    2009-02-01

    The German Mouse Clinic (GMC) is a large scale phenotyping center where mouse mutant lines are analyzed in a standardized and comprehensive way. The result is an almost complete picture of the phenotype of a mouse mutant line--a systemic view. At the GMC, expert scientists from various fields of mouse research work in close cooperation with clinicians side by side at one location. The phenotype screens comprise the following areas: allergy, behavior, clinical chemistry, cardiovascular analyses, dysmorphology, bone and cartilage, energy metabolism, eye and vision, host-pathogen interactions, immunology, lung function, molecular phenotyping, neurology, nociception, steroid metabolism, and pathology. The German Mouse Clinic is an open access platform that offers a collaboration-based phenotyping to the scientific community (www.mouseclinic.de). More than 80 mutant lines have been analyzed in a primary screen for 320 parameters, and for 95% of the mutant lines we have found new or additional phenotypes that were not associated with the mouse line before. Our data contributed to the association of mutant mouse lines to the corresponding human disease. In addition, the systemic phenotype analysis accounts for pleiotropic gene functions and refines previous phenotypic characterizations. This is an important basis for the analysis of underlying disease mechanisms. We are currently setting up a platform that will include environmental challenge tests to decipher genome-environmental interactions in the areas nutrition, exercise, air, stress and infection with different standardized experiments. This will help us to identify genetic predispositions as susceptibility factors for environmental influences.

  19. PET/CT Imaging in Mouse Models of Myocardial Ischemia

    Directory of Open Access Journals (Sweden)

    Sara Gargiulo

    2012-01-01

    Full Text Available Different species have been used to reproduce myocardial infarction models but in the last years mice became the animals of choice for the analysis of several diseases, due to their short life cycle and the possibility of genetic manipulation. Many techniques are currently used for cardiovascular imaging in mice, including X-ray computed tomography (CT, high-resolution ultrasound, magnetic resonance imaging, and nuclear medicine procedures. Cardiac positron emission tomography (PET allows to examine noninvasively, on a molecular level and with high sensitivity, regional changes in myocardial perfusion, metabolism, apoptosis, inflammation, and gene expression or to measure changes in anatomical and functional parameters in heart diseases. Currently hybrid PET/CT scanners for small laboratory animals are available, where CT adds high-resolution anatomical information. This paper reviews mouse models of myocardial infarction and discusses the applications of dedicated PET/CT systems technology, including animal preparation, anesthesia, radiotracers, and images postprocessing.

  20. Analyses of homologous rotavirus infection in the mouse model.

    Science.gov (United States)

    Burns, J W; Krishnaney, A A; Vo, P T; Rouse, R V; Anderson, L J; Greenberg, H B

    1995-02-20

    The group A rotaviruses are significant human and veterinary pathogens in terms of morbidity, mortality, and economic loss. Despite its importance, an effective vaccine remains elusive due at least in part to our incomplete understanding of rotavirus immunity and protection. Both large and small animal model systems have been established to address these issues. One significant drawback of these models is the lack of well-characterized wild-type homologous viruses and their cell culture-adapted variants. We have characterized four strains of murine rotaviruses, EC, EHP, EL, and EW, in the infant and adult mouse model using wild-type isolates and cell culture-adapted variants of each strain. Wild-type murine rotaviruses appear to be equally infectious in infant and adult mice in terms of the intensity and duration of virus shedding following primary infection. Spread of infection to naive cagemates is seen in both age groups. Clearance of shedding following primary infection appears to correlate with the development of virus-specific intestinal IgA. Protective immunity is developed in both infant and adult mice following oral infection as demonstrated by a lack of shedding after subsequent wild-type virus challenge. Cell culture-adapted murine rotaviruses appear to be highly attenuated when administered to naive animals and do not spread efficiently to nonimmune cagemates. The availability of these wild-type and cell culture-adapted virus preparations should allow a more systematic evaluation of rotavirus infection and immunity. Furthermore, future vaccine strategies can be evaluated in the mouse model using several fully virulent homologous viruses for challenge.

  1. Establishment of a Novel Mouse Model of Coronary Microembolization

    Science.gov (United States)

    Cao, Yuan-Yuan; Chen, Zhang-Wei; Jia, Jian-Guo; Chen, Ao; Zhou, You; Ye, Yong; Gao, Yan-Hua; Xia, Yan; Chang, Shu-Fu; Ma, Jian-Ying; Qian, Ju-Ying; Ge, Jun-Bo

    2016-01-01

    Background: Coronary microembolization (CME) has been frequently seen in acute coronary syndromes and percutaneous coronary intervention. Small animal models are required for further studies of CME related to severe prognosis. This study aimed to explore a new mouse model of CME. Methods: The mouse model of CME was established by injecting polystyrene microspheres into the left ventricular chamber during 15-s occlusion of the ascending aorta. Based on the average diameter and dosage used, 30 C57BL/6 male mice were randomly divided into five groups (n = 6 in each): 9 μm/500,000, 9 μm/800,000, 17 μm/200,000, 17 μm/500,000, and sham groups. The postoperative survival and performance of the mice were recorded. The mice were sacrificed 3 or 10 days after the surgery. The heart tissues were harvested for hematoxylin and eosin staining and Masson trichrome staining to compare the extent of inflammatory cellular infiltration and fibrin deposition among groups and for scanning transmission electron microscopic examinations to see the ultrastructural changes after CME. Results: Survival analysis demonstrated that the cumulative survival rate of the 17 μm/500,000 group was significantly lower than that of the sham group (0/6 vs. 6/6, P = 0.001). The cumulative survival rate of the 17 μm/200,000 group was lower than those of the sham and 9 μm groups with no statistical difference (cumulative survival rate of the 17 μm/200,000, 9 μm/800,000, 9 μm/500,000, and sham groups was 4/6, 5/6, 6/6, and 6/6, respectively). The pathological alterations were similar between the 9 μm/500,000 and 9 μm/800,000 groups. The extent of inflammatory cellular infiltration and fibrin deposition was more severe in the 17 μm/200,000 group than in the 9 μm/500,000 and 9 μm/800,000 groups 3 and 10 days after the surgery. Scanning transmission electron microscopic examinations revealed platelet aggregation and adhesion, microthrombi formation, and changes in cardiomyocytes. Conclusion: The

  2. Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis

    NARCIS (Netherlands)

    W.R. Swindell (William R.); A. Johnston (Andrew); S. Carbajal (Steve); G. Han (Gangwen); C.T. Wohn (Christopher); J. Lu (Jun); X. Xing (Xianying); R.P. Nair (Rajan P.); J.J. Voorhees (John); J.T. Elder (James); X.J. Wang (Xian Jiang); S. Sano (Shigetoshi); E.P. Prens (Errol); J. DiGiovanni (John); M.R. Pittelkow (Mark R.); N.L. Ward (Nicole); J.E. Gudjonsson (Johann Eli)

    2011-01-01

    textabstractDevelopment of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features

  3. Human tissue models in cancer research: looking beyond the mouse

    Directory of Open Access Journals (Sweden)

    Samuel J. Jackson

    2017-08-01

    Full Text Available Mouse models, including patient-derived xenograft mice, are widely used to address questions in cancer research. However, there are documented flaws in these models that can result in the misrepresentation of human tumour biology and limit the suitability of the model for translational research. A coordinated effort to promote the more widespread development and use of ‘non-animal human tissue’ models could provide a clinically relevant platform for many cancer studies, maximising the opportunities presented by human tissue resources such as biobanks. A number of key factors limit the wide adoption of non-animal human tissue models in cancer research, including deficiencies in the infrastructure and the technical tools required to collect, transport, store and maintain human tissue for lab use. Another obstacle is the long-standing cultural reliance on animal models, which can make researchers resistant to change, often because of concerns about historical data compatibility and losing ground in a competitive environment while new approaches are embedded in lab practice. There are a wide range of initiatives that aim to address these issues by facilitating data sharing and promoting collaborations between organisations and researchers who work with human tissue. The importance of coordinating biobanks and introducing quality standards is gaining momentum. There is an exciting opportunity to transform cancer drug discovery by optimising the use of human tissue and reducing the reliance on potentially less predictive animal models.

  4. The first knockin mouse model of episodic ataxia type 2.

    Science.gov (United States)

    Rose, Samuel J; Kriener, Lisa H; Heinzer, Ann K; Fan, Xueliang; Raike, Robert S; van den Maagdenberg, Arn M J M; Hess, Ellen J

    2014-11-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Pathogenicity of Conidiobolus coronatus and Fusarium solani in mouse models.

    Science.gov (United States)

    Li, Yadi; Fang, Xiangang; Zhou, Xiaoqian; Geng, Suying; Wang, Yuxin; Yang, Xiumin

    2017-06-01

    To study the pathogenicity of Conidiobolus coronatus (C. coronatus) and Fusarium solani (F. solani) in animal models. Immunocompromised mice were treated with cyclophosphamide and prednisolone via intraperitoneal injection before and after inoculation. According to pathogenic characteristics of different fungi, C. coronatus was used to infect mice via intravenous inoculation, intraperitoneal inoculation, gastrointestinal infusion and intradermal inoculation methods. And F. solani was used to infect mice by inoculation via the abraded or normal skin. In the group of immunocompromised mice, C. coronatus was isolated from the lung tissues of one mouse on day 7 and another on day 10 respectively. The corresponding histopathology revealed infiltration of local inflammatory cells in the lung tissue. Pathogenic lesions were observed in all normal and immunocompromised mice infected with F. solani via abraded skin. The lesions in the immunocompromised mice were more severe and persisted longer than those in the normal mice. Moreover, hyphae were mostly observed in the histopathological examination and fungal culture from the immunocompromised mouse. The pathogenicity of C. coronatus was relatively weak as it did not induce local infections and did not disseminate the disease in immunocompetent and immunocompromised mice. Therefore, F. solani is a type of opportunistic pathogenic fungus, and abraded skin is one of the causative routes of infection. © 2017 Blackwell Verlag GmbH.

  6. Learning delays in a mouse model of Autism Spectrum Disorder.

    Science.gov (United States)

    Rendall, Amanda R; Truong, Dongnhu T; Fitch, R Holly

    2016-04-15

    Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder with core symptoms of atypical social interactions and repetitive behaviors. It has also been reported that individuals with ASD have difficulty with multisensory integration, and this may disrupt higher-order cognitive abilities such as learning and social communication. Impairments in the integration of sensory information could in turn reflect diminished cross-modal white matter connectivity. Moreover, the genetic contribution in ASD appears to be strong, with heritability estimates as high as 90%. However, no single gene has been identified, and over 1000 risk genes have been reported. One of these genes - contactin-associated-like-protein 2 (CNTNAP2) - was first associated with Specific Language Impairment, and more recently has been linked to ASD. CNTNAP2 encodes a cell adhesion protein regulating synaptic signal transmission. To better understand the behavioral and biological underlying mechanisms of ASD, a transgenic mouse model was created with a genetic knockout (KO) of the rodent homolog Cntnap2. Initial studies on this mouse revealed poor social interactions, behavioral perseveration, and reduced vocalizations-all strongly resembling human ASD symptoms. Cntnap2 KO mice also show abnormalities in myelin formation, consistent with a hypo-connectivity model of ASD. The current study was designed to further assess the behavioral phenotype of this mouse model, with a focus on learning and memory. Cntnap2 KO and wild-type mice were tested on a 4/8 radial arm water maze for 14 consecutive days. Error scores (total, working memory, reference memory, initial and repeated reference memory), latency and average turn angle were independently assessed using a 2×14 repeated measures ANOVA. Results showed that Cntnap2 KO mice exhibited significant deficits in working and reference memory during the acquisition period of the task. During the retention period (i.e., after asymptote in errors

  7. Development of a syngeneic mouse model of epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Quinn Bridget A

    2010-10-01

    Full Text Available Abstract Background Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies. Methods Individual lines of TgMISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (TgMISIIR-TAg-Low were isolated that express the oncogenic transgene, but have little or no susceptibility to tumor development. Independent murine ovarian carcinoma (MOVCAR cell lines were established from the ascites of tumor-bearing C57BL/6 TgMISIIR-TAg transgenic mice, characterized and tested for engraftment in the following recipient mice: 1 severe immunocompromised immunodeficient (SCID, 2 wild type C57BL/6, 3 oophorectomized tumor-prone C57BL/6 TgMISIIR-TAg transgenic and 4 non-tumor prone C57BL/6 TgMISIIR-TAg-Low transgenic. Lastly, MOVCAR cells transduced with a luciferase reporter were implanted in TgMISIIR-TAg-Low mice and in vivo tumor growth monitored by non-invasive optical imaging. Results Engraftment of MOVCAR cells by i.p. injection resulted in the development of disseminated peritoneal carcinomatosis in SCID, but not wild type C57BL/6 mice. Oophorectomized tumor-prone TgMISIIR-TAg mice developed peritoneal carcinomas with high frequency, rendering them unsuitable as allograft recipients. Orthotopic or pseudo-orthotopic implantation of MOVCAR cells in TgMISIIR-TAg-Low mice resulted in the development of disseminated peritoneal tumors, frequently accompanied by the production of malignant ascites. Tumors arising in the engrafted mice bore histopathological resemblance to human high-grade serous EOC and exhibited a similar pattern

  8. Quantification of Brain Access of Exendin-4 in the C57BL Mouse Model by SPIM Fluorescence Imaging and the Allen Mouse Brain Reference Model

    DEFF Research Database (Denmark)

    Jensen, Casper Bo; Secher, Anna; Hecksher-Sørensen, Jacob

    2015-01-01

    construct a SPIM brain atlas based on the Allen mouse brain 3D reference model and use it to analyze the access of peripherally injected Exendin-4 into the brain compared to a negative control group. The constructed atlas consists of an average SPIM volume obtained from eight C57BL mouse brains using group......-wise registration. A cross-modality registration is performed between the constructed average volume and the Allen mouse brain reference model to allow propagation of annotations to the SPIM average brain. Finally, manual corrections of the annotations are performed and validated by visual inspection. The study...

  9. Neuroprotection in a novel mouse model of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Katie Lidster

    Full Text Available Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment.

  10. Nutritional factors in a mouse model of Rett syndrome.

    Science.gov (United States)

    Nag, Nupur; Ward, Bonnie; Berger-Sweeney, Joanne E

    2009-04-01

    Environmental factors such as nutrition and housing can influence behavioral and anatomical characteristics of several neurological disorders, including Rett syndrome (RTT). RTT is associated with mutations in the X-linked gene encoding MeCP2, a transcriptional repressor that binds methylated DNA. While direct genetic intervention in humans is impossible at this time, motor and cognitive deficits in RTT may be ameliorated through manipulations of epigenetic/environmental factors. For example, studies in rodents suggest that choline nutrient supplementation during critical periods of brain development enhances cholinergic neurotransmission, alters neuronal size and distribution, and facilitates performance of memory and motoric tasks. Recent work in a mouse model of RTT shows that enhancing maternal nutrition through choline supplementation improves both anatomical and behavioral symptoms in the mutant offspring. We describe here cellular and molecular mechanisms that may underlie this specific enhancement and may provide more general insights into mechanisms underlying gene-environment interactions in neurological disorders.

  11. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations

    NARCIS (Netherlands)

    Hruban, Ralph H.; Adsay, N. Volkan; Albores-Saavedra, Jorge; Anver, Miriam R.; Biankin, Andrew V.; Boivin, Gregory P.; Furth, Emma E.; Furukawa, Toru; Klein, Alison; Klimstra, David S.; Kloppel, Gunter; Lauwers, Gregory Y.; Longnecker, Daniel S.; Luttges, Jutta; Maitra, Anirban; Offerhaus, G. Johan A.; Pérez-Gallego, Lucía; Redston, Mark; Tuveson, David A.

    2006-01-01

    Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The

  12. Generation and characterization of an inducible transgenic model for studying mouse esophageal biology

    NARCIS (Netherlands)

    S.G. Roth (Sabrina); P.F. Franken (Patrick); K. Monkhorst (Kim); J. Kong-a-San (John); R. Fodde (Riccardo)

    2012-01-01

    textabstractBackground: To facilitate the in vivo study of esophageal (stem) cell biology in homeostasis and cancer, novel mouse models are necessary to elicit expression of candidate genes in a tissue-specific and inducible fashion. To this aim, we developed and studied a mouse model to allow

  13. A STAT-1 knockout mouse model for Machupo virus pathogenesis

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    Shurtleff Amy C

    2011-06-01

    Full Text Available Abstract Background Machupo virus (MACV, a member of the Arenaviridae, causes Bolivian hemorrhagic fever, with ~20% lethality in humans. The pathogenesis of MACV infection is poorly understood, and there are no clinically proven treatments for disease. This is due, in part, to a paucity of small animal models for MACV infection in which to discover and explore candidate therapeutics. Methods Mice lacking signal transducer and activator of transcription 1 (STAT-1 were infected with MACV. Lethality, viral replication, metabolic changes, hematology, histopathology, and systemic cytokine expression were analyzed throughout the course of infection. Results We report here that STAT-1 knockout mice succumbed to MACV infection within 7-8 days, and presented some relevant clinical and histopathological manifestations of disease. Furthermore, the model was used to validate the efficacy of ribavirin in protection against infection. Conclusions The STAT-1 knockout mouse model can be a useful small animal model for drug testing and preliminary immunological analysis of lethal MACV infection.

  14. Genetically engineered mouse models in oncology research and cancer medicine.

    Science.gov (United States)

    Kersten, Kelly; de Visser, Karin E; van Miltenburg, Martine H; Jonkers, Jos

    2017-02-01

    Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune-proficient microenvironment. Tumors arising in advanced GEMMs closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start. Given that GEMMs capture both tumor cell-intrinsic and cell-extrinsic factors that drive de novo tumor initiation and progression toward metastatic disease, these models are indispensable for preclinical research. GEMMs have successfully been used to validate candidate cancer genes and drug targets, assess therapy efficacy, dissect the impact of the tumor microenvironment, and evaluate mechanisms of drug resistance. In vivo validation of candidate cancer genes and therapeutic targets is further accelerated by recent advances in genetic engineering that enable fast-track generation and fine-tuning of GEMMs to more closely resemble human patients. In addition, aligning preclinical tumor intervention studies in advanced GEMMs with clinical studies in patients is expected to accelerate the development of novel therapeutic strategies and their translation into the clinic. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  15. A new model for Hendra virus encephalitis in the mouse.

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    Johanna Dups

    Full Text Available Hendra virus (HeV infection in humans is characterized by an influenza like illness, which may progress to pneumonia or encephalitis and lead to death. The pathogenesis of HeV infection is poorly understood, and the lack of a mouse model has limited the opportunities for pathogenetic research. In this project we reassessed the role of mice as an animal model for HeV infection and found that mice are susceptible to HeV infection after intranasal exposure, with aged mice reliably developing encephalitic disease. We propose an anterograde route of neuroinvasion to the brain, possibly along olfactory nerves. This is supported by evidence for the development of encephalitis in the absence of viremia and the sequential distribution of viral antigen along pathways of olfaction in the brain of intranasally challenged animals. In our studies mice developed transient lower respiratory tract infection without progressing to viremia and systemic vasculitis that is common to other animal models. These studies report a new animal model of HeV encephalitis that will allow more detailed studies of the neuropathogenesis of HeV infection, particularly the mode of viral spread and possible sequestration within the central nervous system; investigation of mechanisms that moderate the development of viremia and systemic disease; and inform the development of improved treatment options for human patients.

  16. Stochastic model of Tsc1 lesions in mouse brain.

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    Shilpa Prabhakar

    Full Text Available Tuberous sclerosis complex (TSC is an autosomal dominant disorder due to mutations in either TSC1 or TSC2 that affects many organs with hamartomas and tumors. TSC-associated brain lesions include subependymal nodules, subependymal giant cell astrocytomas and tubers. Neurologic manifestations in TSC comprise a high frequency of mental retardation and developmental disorders including autism, as well as epilepsy. Here, we describe a new mouse model of TSC brain lesions in which complete loss of Tsc1 is achieved in multiple brain cell types in a stochastic pattern. Injection of an adeno-associated virus vector encoding Cre recombinase into the cerebral ventricles of mice homozygous for a Tsc1 conditional allele on the day of birth led to reduced survival, and pathologic findings of enlarged neurons, cortical heterotopias, subependymal nodules, and hydrocephalus. The severity of clinical and pathologic findings as well as survival was shown to be dependent upon the dose and serotype of Cre virus injected. Although several other models of TSC brain disease exist, this model is unique in that the pathology reflects a variety of TSC-associated lesions involving different numbers and types of cells. This model provides a valuable and unique addition for therapeutic assessment.

  17. Mouse model of Timothy syndrome recapitulates triad of autistic traits.

    Science.gov (United States)

    Bader, Patrick L; Faizi, Mehrdad; Kim, Leo H; Owen, Scott F; Tadross, Michael R; Alfa, Ronald W; Bett, Glenna C L; Tsien, Richard W; Rasmusson, Randall L; Shamloo, Mehrdad

    2011-09-13

    Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca(V)1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca(V)1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tone-cued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.

  18. Sleep phenotyping in a mouse model of extreme trait anxiety.

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    Vladimira Jakubcakova

    Full Text Available BACKGROUND: There is accumulating evidence that anxiety impairs sleep. However, due to high sleep variability in anxiety disorders, it has been difficult to state particular changes in sleep parameters caused by anxiety. Sleep profiling in an animal model with extremely high vs. low levels of trait anxiety might serve to further define sleep patterns associated with this psychopathology. METHODOLOGY/PRINCIPAL FINDINGS: Sleep-wake behavior in mouse lines with high (HAB, low (LAB and normal (NAB anxiety-related behaviors was monitored for 24 h during baseline and recovery after 6 h sleep deprivation (SD. The amounts of each vigilance state, sleep architecture, and EEG spectral variations were compared between the mouse lines. In comparison to NAB mice, HAB mice slept more and exhibited consistently increased delta power during non-rapid eye movement (NREM sleep. Their sleep patterns were characterized by heavy fragmentation, reduced maintenance of wakefulness, and frequent intrusions of rapid eye movement (REM sleep. In contrast, LAB mice showed a robust sleep-wake rhythm with remarkably prolonged sleep latency and a long, persistent period of wakefulness. In addition, the accumulation of delta power after SD was impaired in the LAB line, as compared to HAB mice. CONCLUSIONS/SIGNIFICANCE: Sleep-wake patterns were significantly different between HAB and LAB mice, indicating that the genetic predisposition to extremes in trait anxiety leaves a biological scar on sleep quality. The enhanced sleep demand observed in HAB mice, with a strong drive toward REM sleep, may resemble a unique phenotype reflecting not only elevated anxiety but also a depression-like attribute.

  19. Iodine uptake and prostate cancer in the TRAMP mouse model.

    Science.gov (United States)

    Olvera-Caltzontzin, Paloma; Delgado, Guadalupe; Aceves, Carmen; Anguiano, Brenda

    2013-11-08

    Iodine supplementation exerts antitumor effects in several types of cancer. Iodide (I⁻) and iodine (I₂) reduce cell proliferation and induce apoptosis in human prostate cancer cells (LNCaP and DU-145). Both chemical species decrease tumor growth in athymic mice xenografted with DU-145 cells. The aim of this study was to analyze the uptake and effects of iodine in a preclinical model of prostate cancer (transgenic adenocarcinoma of the mouse prostate [TRAMP] mice/SV40-TAG antigens), which develops cancer by 12 wks of age. ¹²⁵I⁻ and ¹²⁵I₂ uptake was analyzed in prostates from wild-type and TRAMP mice of 12 and 24 wks in the presence of perchlorate (inhibitor of the Na⁺/I⁻ symporter [NIS]). NIS expression was quantified by quantitative polymerase chain reaction (qPCR). Mice (6 wks old) were supplemented with 0.125 mg I⁻ plus 0.062 mg I₂/mouse/day for 12 or 24 wks. The weight of the genitourinary tract (GUT), the number of acini with lesions, cell proliferation (levels of proliferating cell nuclear antigen [PCNA] by immunohistochemistry), p53 and p21 expression (by qPCR) and apoptosis (relative amount of nucleosomes by enzyme-linked immunosorbent assay) were evaluated. In both age-groups, normal and tumoral prostates take up both forms of iodine, but only I⁻ uptake was blocked by perchlorate. Iodine supplementation prevented the overexpression of NIS in the TRAMP mice, but had no effect on the GUT weight, cell phenotype, proliferation or apoptosis. In TRAMP mice, iodine increased p53 expression but had no effect on p21 (a p53-dependent gene). Our data corroborate NIS involvement in I⁻ uptake and support the notion that another transporter mediates I₂ uptake. Iodine did not prevent cancer progression. This result could be explained by a strong inactivation of the p53 pathway by TAG antigens.

  20. A new mouse model for female genital schistosomiasis.

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    Monica L Richardson

    2014-05-01

    Full Text Available Over 112 million people worldwide are infected with Schistosoma haematobium, one of the most prevalent schistosome species affecting humans. Female genital schistosomiasis (FGS occurs when S. haematobium eggs are deposited into the female reproductive tract by adult worms, which can lead to pelvic pain, vaginal bleeding, genital disfigurement and infertility. Recent evidence suggests co-infection with S. haematobium increases the risks of contracting sexually transmitted diseases such as HIV. The associated mechanisms remain unclear due to the lack of a tractable animal model. We sought to create a mouse model conducive to the study of immune modulation and genitourinary changes that occur with FGS.To model FGS in mice, we injected S. haematobium eggs into the posterior vaginal walls of 30 female BALB/c mice. A control group of 20 female BALB/c mice were injected with uninfected LVG hamster tissue extract. Histology, flow cytometry and serum cytokine levels were assessed at 2, 4, 6, and 8 weeks post egg injection. Voiding studies were performed at 1 week post egg injection.Vaginal wall injection with S. haematobium eggs resulted in synchronous vaginal granuloma development within 2 weeks post-egg injection that persisted for at least 6 additional weeks. Flow cytometric analysis of vaginal granulomata revealed infiltration by CD4+ T cells with variable expression of the HIV co-receptors CXCR4 and CCR5. Granulomata also contained CD11b+F4/80+ cells (macrophages and eosinophils as well as CXCR4+MerTK+ macrophages. Strikingly, vaginal wall-injected mice featured significant urinary frequency despite the posterior vagina being anatomically distant from the bladder. This may represent a previously unrecognized overactive bladder response to deposition of schistosome eggs in the vagina.We have established a new mouse model that could potentially enable novel studies of genital schistosomiasis in females. Ongoing studies will further explore the

  1. Altered Cortical Ensembles in Mouse Models of Schizophrenia.

    Science.gov (United States)

    Hamm, Jordan P; Peterka, Darcy S; Gogos, Joseph A; Yuste, Rafael

    2017-04-05

    In schizophrenia, brain-wide alterations have been identified at the molecular and cellular levels, yet how these phenomena affect cortical circuit activity remains unclear. We studied two mouse models of schizophrenia-relevant disease processes: chronic ketamine (KET) administration and Df(16)A +/- , modeling 22q11.2 microdeletions, a genetic variant highly penetrant for schizophrenia. Local field potential recordings in visual cortex confirmed gamma-band abnormalities similar to patient studies. Two-photon calcium imaging of local cortical populations revealed in both models a deficit in the reliability of neuronal coactivity patterns (ensembles), which was not a simple consequence of altered single-neuron activity. This effect was present in ongoing and sensory-evoked activity and was not replicated by acute ketamine administration or pharmacogenetic parvalbumin-interneuron suppression. These results are consistent with the hypothesis that schizophrenia is an "attractor" disease and demonstrate that degraded neuronal ensembles are a common consequence of diverse genetic, cellular, and synaptic alterations seen in chronic schizophrenia. Published by Elsevier Inc.

  2. Indirubin Treatment of Lipopolysaccharide-Induced Mastitis in a Mouse Model and Activity in Mouse Mammary Epithelial Cells.

    Science.gov (United States)

    Lai, Jin-Lun; Liu, Yu-Hui; Peng, Yong-Chong; Ge, Pan; He, Chen-Fei; Liu, Chang; Chen, Ying-Yu; Guo, Ai-Zhen; Hu, Chang-Min

    2017-01-01

    Indirubin is a Chinese medicine extracted from indigo and known to be effective for treating chronic myelogenous leukemia, neoplasia, and inflammatory disease. This study evaluated the in vivo anti-inflammatory activity of indirubin in a lipopolysaccharide- (LPS-) induced mouse mastitis model. The indirubin mechanism and targets were evaluated in vitro in mouse mammary epithelial cells. In the mouse model, indirubin significantly attenuated the severity of inflammatory lesions, edema, inflammatory hyperemia, milk stasis and local tissue necrosis, and neutrophil infiltration. Indirubin significantly decreased myeloperoxidase activity and downregulated the production of tumor necrosis factor- α , interleukin-1 β (IL-1 β ), and IL-6 caused by LPS. In vitro, indirubin inhibited LPS-stimulated expression of proinflammatory cytokines in a dose-dependent manner. It also downregulated LPS-induced toll-like receptor 4 (TLR4) expression and inhibited phosphorylation of LPS-induced nuclear transcription factor-kappa B (NF- κ B) P65 protein and inhibitor of kappa B. In addition to its effect on the NF- κ B signaling pathway, indirubin suppressed the mitogen-activated protein kinase (MAPK) signaling by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK), P38, and c-jun NH2-terminal kinase (JNK). Indirubin improved LPS-induced mouse mastitis by suppressing TLR4 and downstream NF- κ B and MAPK pathway inflammatory signals and might be a potential treatment of mastitis and other inflammatory diseases.

  3. Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis

    Science.gov (United States)

    Swindell, William R.; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P.; Voorhees, John J.; Elder, James T.; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P.; DiGiovanni, John; Pittelkow, Mark R.; Ward, Nicole L.; Gudjonsson, Johann E.

    2011-01-01

    Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. PMID:21483750

  4. A comparison of the mouse and human lipoproteome: suitability of the mouse model for studies of human lipoproteins.

    Science.gov (United States)

    Gordon, Scott M; Li, Hailong; Zhu, Xiaoting; Shah, Amy S; Lu, L Jason; Davidson, W Sean

    2015-06-05

    Plasma levels of low density lipoproteins (LDL) and high density lipoproteins (HDL) exhibit opposing associations with cardiovascular disease in human populations and mouse models have been heavily used to derive a mechanistic understanding of these relationships. In humans, recent mass spectrometry studies have revealed that the plasma lipoproteome is significantly more complex than originally appreciated. This is particularly true for HDL which contains some 90 distinct proteins, a majority of which play functional roles that go beyond those expected for simple lipid transport. Unfortunately, the mouse lipoproteome remains largely uncharacterized-a significant gap given the heavy reliance on the model. Using a gel filtration chromatography and mass spectrometry analysis that targets phospholipid-bound plasma proteins, we compared the mouse lipoproteome and its size distribution to a previous, identical human analysis. We identified 113 lipid associated proteins in the mouse. In general, the protein diversity in the LDL and HDL size ranges was similar in mice versus humans, though some distinct differences were noted. For the majority of proteins, the size distributions, that is, whether a given protein was associated with large versus small HDL particles, for example, were also similar between species. Again, however, there were clear differences exhibited by a minority of proteins that may reflect metabolic differences between species. Finally, by correlating the lipid and protein size profiles, we identified five proteins that closely track with the major HDL protein, apolipoprotein A-I across both species. Thus, mice have most of the minor proteins identified in human lipoproteins that play key roles in inflammation, innate immunity, proteolysis and its inhibition, and vitamin transport. This provides support for the continued use of the mouse as a model for many aspects of human lipoprotein metabolism.

  5. Single and Multiple Gene Manipulations in Mouse Models of Human Cancer

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    Heather L. Lehman

    2015-01-01

    Full Text Available Mouse models of human cancer play a critical role in understanding the molecular and cellular mechanisms of tumorigenesis. Advances continue to be made in modeling human disease in a mouse, though the relevance of a mouse model often relies on how closely it is able to mimic the histologic, molecular, and physiologic characteristics of the respective human cancer. A classic use of a genetically engineered mouse in studying cancer is through the overexpression or deletion of a gene. However, the manipulation of a single gene often falls short of mimicking all the characteristics of the carcinoma in humans; thus a multiple gene approach is needed. Here we review genetic mouse models of cancers and their abilities to recapitulate human carcinoma with single versus combinatorial approaches with genes commonly involved in cancer.

  6. The mouse gut microbiome revisited: From complex diversity to model ecosystems.

    Science.gov (United States)

    Clavel, Thomas; Lagkouvardos, Ilias; Blaut, Michael; Stecher, Bärbel

    2016-08-01

    Laboratory mice are the most commonly used animal model in translational medical research. In recent years, the impact of the gut microbiota (i.e. communities of microorganisms in the intestine) on host physiology and the onset of diseases, including metabolic and neuronal disorders, cancers, gastrointestinal infections and chronic inflammation, became a focal point of interest. There is abundant evidence that mouse phenotypes in disease models vary greatly between animal facilities or commercial providers, and that this variation is associated with differences in the microbiota. Hence, there is a clear discrepancy between the widespread use of mouse models in research and the patchwork knowledge on the mouse gut microbiome. In the present manuscript, we summarize data pertaining to the diversity and functions of the mouse gut microbiota, review existing work on gnotobiotic mouse models, and discuss challenges and opportunities for current and future research in the field. Copyright © 2016 Elsevier GmbH. All rights reserved.

  7. Using the mouse to model human disease: increasing validity and reproducibility

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    Monica J. Justice

    2016-02-01

    Full Text Available Experiments that use the mouse as a model for disease have recently come under scrutiny because of the repeated failure of data, particularly derived from preclinical studies, to be replicated or translated to humans. The usefulness of mouse models has been questioned because of irreproducibility and poor recapitulation of human conditions. Newer studies, however, point to bias in reporting results and improper data analysis as key factors that limit reproducibility and validity of preclinical mouse research. Inaccurate and incomplete descriptions of experimental conditions also contribute. Here, we provide guidance on best practice in mouse experimentation, focusing on appropriate selection and validation of the model, sources of variation and their influence on phenotypic outcomes, minimum requirements for control sets, and the importance of rigorous statistics. Our goal is to raise the standards in mouse disease modeling to enhance reproducibility, reliability and clinical translation of findings.

  8. Mechanistically distinct mouse models for CRX-associated retinopathy.

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    Nicholas M Tran

    2014-02-01

    Full Text Available Cone-rod homeobox (CRX protein is a "paired-like" homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP, Cone-Rod Dystrophy (CoRD and Leber Congenital Amaurosis (LCA, with variable severity. Heterozygous Crx Knock-Out (KO mice ("+/-" have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN mouse models: Crx(E168d2 ("E168d2" and Crx(R90W ("R90W". E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 ("E168d2/+" but not R90W ("R90W/+" mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/- mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX([E168d2] and CRX([R90W] proteins fail to activate transcription in vitro, but CRX([E168d2] interferes more strongly with the function of wild type (WT CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of novel

  9. Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

    Science.gov (United States)

    Tran, Nicholas M.; Zhang, Alan; Zhang, Xiaodong; Huecker, Julie B.; Hennig, Anne K.; Chen, Shiming

    2014-01-01

    Cone-rod homeobox (CRX) protein is a “paired-like” homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice (“+/−”) have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: CrxE168d2 (“E168d2”) and CrxR90W (“R90W”). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 (“E168d2/+”) but not R90W (“R90W/+”) mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/− mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX[E168d2] and CRX[R90W] proteins fail to activate transcription in vitro, but CRX[E168d2] interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of

  10. Spontaneous rescue from cystic fibrosis in a mouse model

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    Stanke Frauke

    2006-03-01

    Full Text Available Abstract Background From the original CftrTgH(neoimHgu mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1 we have generated two inbred CftrTgH(neoimHgu mutant strains named CF/1-CftrTgH(neoimHgu and CF/3-CftrTgH(neoimHgu, which are fertile and show normal growth and lifespan. Initial genome wide scan analysis with microsatellite markers indicated that the two inbred strains differed on the genetic level. In order to further investigate whether these genetic differences have an impact on the disease phenotype of cystic fibrosis we characterised the phenotype of the two inbred strains. Results Reduced amounts, compared to wild type control animals, of correctly spliced Cftr mRNA were detected in the nasal epithelia, lungs and the intestine of both inbred CftrTgH(neoimHgu strains, with higher residual amount observed for CF/1-CftrTgH(neoimHgu than CF/3-CftrTgH(neoimHgu for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-CftrTgH(neoimHgu and 4% for CF/3-CftrTgH(neoimHgu. Unlike the apparent strain and/or tissue specific regulation of Cftr mRNA splicing, short circuit current measurements in the respiratory and intestinal epithelium revealed that both strains have ameliorated the basic defect of cystic fibrosis with a presentation of a normal electrophysiology in both tissues. Conclusion Unlike the outbred CftrTgH(neoimHgu insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred CftrTgH(neoimHgu strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-CftrTgH(neoimHgu and CF/3-CftrTgH(neoimHgu offer an excellent model whereby determination of the minimal levels of protein required for the restoration of the basic defect of cystic fibrosis can be studied, along with the modulating factors which may affect this

  11. Rapid target gene validation in complex cancer mouse models using re‐derived embryonic stem cells

    National Research Council Canada - National Science Library

    Huijbers, Ivo J; Bin Ali, Rahmen; Pritchard, Colin; Cozijnsen, Miranda; Kwon, Min‐Chul; Proost, Natalie; Song, Ji‐Ying; Vries, Hilda; Badhai, Jitendra; Sutherland, Kate; Krimpenfort, Paul; Michalak, Ewa M; Jonkers, Jos; Berns, Anton

    2014-01-01

    Human cancers modeled in Genetically Engineered Mouse Models ( GEMM s) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies...

  12. Deficient Sleep in Mouse Models of Fragile X Syndrome

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    R. Michelle Saré

    2017-09-01

    Full Text Available In patients with fragile X syndrome (FXS, sleep problems are commonly observed but are not well characterized. In animal models of FXS (dfmr1 and Fmr1 knockout (KO/Fxr2 heterozygote circadian rhythmicity is affected, but sleep per se has not been examined. We used a home-cage monitoring system to assess total sleep time in both light and dark phases in Fmr1 KO mice at different developmental stages. Fmr1 KOs at P21 do not differ from controls, but genotype × phase interactions in both adult (P70 and P180 groups are statistically significant indicating that sleep in Fmr1 KOs is reduced selectively in the light phase compared to controls. Our results show the emergence of abnormal sleep in Fmr1 KOs during the later stages of brain maturation. Treatment of adult Fmr1 KO mice with a GABAB agonist, R-baclofen, did not restore sleep duration in the light phase. In adult (P70 Fmr1 KO/Fxr2 heterozygote animals, total sleep time was further reduced, once again in the light phase. Our data highlight the importance of the fragile X genes (Fmr1 and Fxr2 in sleep physiology and confirm the utility of these mouse models in enhancing our understanding of sleep disorders in FXS.

  13. Dermal lymphatic dilation in a mouse model of alopecia areata

    Science.gov (United States)

    Sundberg, John P.; Pratt, C. Herbert; Silva, Kathleen A.; Kennedy, Victoria E.; Stearns, Timothy; Sundberg, Beth A.; King, Lloyd E.; HogenEsch, Harm

    2016-01-01

    Mouse models of various types of inflammatory skin disease are often accompanied by increased dermal angiogenesis. The C3H/HeJ inbred strain spontaneously develops alopecia areata (AA), a cell mediated autoimmune disorder that can be controllably expanded using full thickness skin grafts to young unaffected mice. This provides a reproducible and progressive model for AA in which the vascularization of the skin can be examined. Mice receiving skin grafts from AA or normal mice were evaluated at 5, 10, 15, and 20 weeks after engraftment. Lymphatics are often overlooked as they are small slit-like structures above the hair follicle that resemble artifact-like separation of collagen bundles with some fixatives. Lymphatics are easily detected using lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) by immunohistochemistry to label their endothelial cells. Using LYVE1, there were no changes in distribution or numbers of lymphatics although they were more prominent (dilated) in the mice with AA. Lyve1 transcripts were not significantly upregulated except at 10 weeks after skin grafting when clinical signs of AA first become apparent. Other genes involved with vascular growth and dilation or movement of immune cells were dysregulated, mostly upregulated. These findings emphasize aspects of AA not commonly considered and provide potential targets for therapeutic intervention. PMID:26960166

  14. The gut microbiota in mouse models of inflammatory bowel disease.

    Science.gov (United States)

    Gkouskou, Kalliopi K; Deligianni, Chrysoula; Tsatsanis, Christos; Eliopoulos, Aristides G

    2014-01-01

    The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD.

  15. The gut microbiota in mouse models of inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Kalliopi eGkouskou

    2014-02-01

    Full Text Available The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of inflammatory bowel diseases have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn’s disease and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of inflammatory bowel diseases.

  16. Establishment of Orthotopic Lewis Lung Cancer Model in Mouse

    Directory of Open Access Journals (Sweden)

    Xicai WANG

    2010-01-01

    Full Text Available Background and objective The mouse lung cancer orthotopic model includes spontaneous lung cancer model and endotracheal transplanted model, and etc. The spontaneous lung cancer needs longer time and does not ensure the rate of the generation of the tumor; as for endotracheal transplanted model, the position and size of the tumor are instable. In this study, the 3LL cell line was orthotopically transplanted into the lung of the C57BL/6 mice, compare to the heterotopic model, to discuss their stability and transfer-characteristics. And this study was also to optimize the method of establishing lung cancer orthotopic animal model. Methods Different quantity of 3LL cells were inoculated into the left oxter of C57BL/6 mice to establish the heterotopic model; or suspended with Matrigel then inoculated into the left lung of C57BL/6 mice to establish orthotopic model. The survival-time of the mice was examined. The tissue was collected for the subsequent histology assay after euthanizing the mice. Microvessels density (MVD was observed and counted by immunohistological chemistry. CD44v was detected by flow cytometry. Results TTumor-form-rate of the heterotopic group were 100%, 66.7%, 16.7%, respectively, and had no macroscopic transfer. Tumor-form-rate of the orthotopic group were 100%, 100%, 83.3%, respectively, and had widespread transfer in contralateral chest and the lung. The median survival time of the orthotopic group ( 38, 35, 23 days were less than the heterotopic group (82, 72, 50 days. MVD of the orthotopic group (120.2±9.73 was higher than the heterotopic group (92.6±7.12. The expression of CD44v of orthotopic (26.46± 1.56% was higher than the heterotopic group (23.13±1.02%. Conclusion The lung cancer orthotopic model which established by 3LL cells transplanted into the lung of the mice is simple, dependable, repeatable and has stronger transfer characteristics than the heterotopic model.

  17. Structure guided homology model based design and engineering of mouse antibodies for humanization.

    Science.gov (United States)

    Kurella, Vinodh B; Gali, Reddy

    2014-01-01

    No universal strategy exists for humanizing mouse antibodies, and most approaches are based on primary sequence alignment and grafting. Although this strategy theoretically decreases the immunogenicity of mouse antibodies, it neither addresses conformational changes nor steric clashes that arise due to grafting of human germline frameworks to accommodate mouse CDR regions. To address these issues, we created and tested a structure-based biologic design approach using a de novo homology model to aid in the humanization of 17 unique mouse antibodies. Our approach included building a structure-based de novo homology model from the primary mouse antibody sequence, mutation of the mouse framework residues to the closest human germline sequence and energy minimization by simulated annealing on the humanized homology model. Certain residues displayed force field errors and revealed steric clashes upon closer examination. Therefore, further mutations were introduced to rationally correct these errors. In conclusion, use of de novo antibody homology modeling together with simulated annealing improved the ability to predict conformational and steric clashes that may arise due to conversion of a mouse antibody into the humanized form and would prevent its neutralization when administered in vivo. This design provides a robust path towards the development of a universal strategy for humanization of mouse antibodies using computationally derived antibody homologous structures.

  18. Sparse Statistical Deformation Model for the Analysis of Craniofacial Malformations in the Crouzon Mouse

    DEFF Research Database (Denmark)

    Ólafsdóttir, Hildur; Hansen, Michael Sass; Sjöstrand, Karl

    2007-01-01

    Crouzon syndrome is characterised by the premature fusion of cranial sutures. Recently the first genetic Crouzon mouse model was generated. In this study, Micro CT skull scannings of wild-type mice and Crouzon mice were investigated. Using nonrigid registration, a wild-type mouse atlas was built....

  19. Modeling transcranial electric stimulation in mouse: a high resolution finite element study.

    Science.gov (United States)

    Bernabei, John M; Lee, Won Hee; Peterchev, Angel V

    2014-01-01

    Mouse models are widely used in studies of various forms of transcranial electric stimulation (TES). However, there is limited knowledge of the electric field distribution induced by TES in mice, and computational models to estimate this distribution are lacking. This study examines the electric field and current density distribution in the mouse brain induced by TES. We created a high-resolution finite element mouse model incorporating ear clip electrodes commonly used in mouse TES to study, for example, electroconvulsive therapy (ECT). The electric field strength and current density induced by an ear clip electrode configuration were computed in the anatomically realistic, inhomogenous mouse model. The results show that the median electric field strength induced in the brain at 1 mA of stimulus current is 5.57 V/m, and the strongest field of 20.19 V/m was observed in the cerebellum. Therefore, to match the median electric field in human ECT at 800 mA current, the electrode current in mouse should be set to approximately 15 mA. However, the location of the strongest electric field in posterior brain regions in the mouse does not model well human ECT which targets more frontal regions. Therefore, the ear clip electrode configuration may not be a good model of human ECT. Using high-resolution realistic models for simulating TES in mice may guide the establishment of appropriate stimulation parameters for future in vivo studies.

  20. Innovations in phenotyping of mouse models in the German Mouse Clinic.

    Science.gov (United States)

    Fuchs, Helmut; Gailus-Durner, Valérie; Neschen, Susanne; Adler, Thure; Afonso, Luciana Caminha; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Bohla, Alexander; Calzada-Wack, Julia; Cohrs, Christian; Dewert, Anna; Fridrich, Barbara; Garrett, Lillian; Glasl, Lisa; Götz, Alexander; Hans, Wolfgang; Hölter, Sabine M; Horsch, Marion; Hurt, Anja; Janas, Eva; Janik, Dirk; Kahle, Melanie; Kistler, Martin; Klein-Rodewald, Tanja; Lengger, Christoph; Ludwig, Tonia; Maier, Holger; Marschall, Susan; Micklich, Kateryna; Möller, Gabriele; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rácz, Ildikó; Räss, Michael; Rathkolb, Birgit; Rozman, Jan; Scheerer, Markus; Schiller, Evelyn; Schrewe, Anja; Steinkamp, Ralph; Stöger, Claudia; Sun, Minxuan; Szymczak, Wilfried; Treise, Irina; Vargas Panesso, Ingrid Liliana; Vernaleken, Alexandra M; Willershäuser, Monja; Wolff-Muscate, Annemarie; Zeh, Ramona; Adamski, Jerzy; Beckers, Johannes; Bekeredjian, Raffi; Busch, Dirk H; Eickelberg, Oliver; Favor, Jack; Graw, Jochen; Höfler, Heinz; Höschen, Christoph; Katus, Hugo; Klingenspor, Martin; Klopstock, Thomas; Neff, Frauke; Ollert, Markus; Schulz, Holger; Stöger, Tobias; Wolf, Eckhard; Wurst, Wolfgang; Yildirim, Ali Önder; Zimmer, Andreas; Hrabě de Angelis, Martin

    2012-10-01

    Under the label of the German Mouse Clinic (GMC), a concept has been developed and implemented that allows the better understanding of human diseases on the pathophysiological and molecular level. This includes better understanding of the crosstalk between different organs, pleiotropy of genes, and the systemic impact of envirotypes and drugs. In the GMC, experts from various fields of mouse genetics and physiology, in close collaboration with clinicians, work side by side under one roof. The GMC is an open-access platform for the scientific community by providing phenotypic analysis in bilateral collaborations ("bottom-up projects") and as a partner and driver in international large-scale biology projects ("top-down projects"). Furthermore, technology development is a major topic in the GMC. Innovative techniques for primary and secondary screens are developed and implemented into the phenotyping pipelines (e.g., detection of volatile organic compounds, VOCs).

  1. Impaired peripheral nerve regeneration in type-2 diabetic mouse model.

    Science.gov (United States)

    Pham, Vuong M; Tu, Nguyen Huu; Katano, Tayo; Matsumura, Shinji; Saito, Akira; Yamada, Akihiro; Furue, Hidemasa; Ito, Seiji

    2018-01-01

    Peripheral neuropathy is one of the most common and serious complications of type-2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, that is, impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. This study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  2. [Protective effect of nicotinamide in a mouse Parkinson's disease model].

    Science.gov (United States)

    Xu, Jing; Xu, Sheng-quan; Liang, Jie; Lu, Yuan; Luo, Jian-hong; Jin, Jing-hua

    2012-03-01

    To examine the protective effect of nicotinamide on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in mouse model and its mechanisms. Parkinson's disease was induced by injection of MPTP in adult male C57BL/6 mice, nicotinamide (500 mg/kg,i.p.) was given prior to subacute (30 mg/kg/d × 5 d,i.p.) MPTP administration. Locomotor activities, striatal dopamine levels, lactate dehydrogenase (LDH) and NO synthase (NOS) activities of whole brains and striatum were analyzed at d5 after last MPTP injections. Pretreatment with nicotinamide significantly improved the locomotor activity in the open-field test (Pclimbing test. Nicotinamide administration resulted in sparing striatal dopamine levels from MPTP-induced dopamine depletion. There was no significant difference in LDH and NOS activities in the whole brains among the groups; but the activities in the striatum were drastically elevated after MPTP treatment. Nicotinamide pretreatment markedly inhibited MPTP-induced LDH and NOS activities (P0.05). Nicotinamide protects dopaminergic neurons against MPTP-induced neurodegeneration,which suggests that the neuroprotective effects be associated with the inhibition of cell injuries and NOS activities.

  3. Increased opioid dependence in a mouse model of panic disorder.

    Science.gov (United States)

    Gallego, Xavier; Murtra, Patricia; Zamalloa, Teresa; Canals, Josep Maria; Pineda, Joseba; Amador-Arjona, Alejandro; Maldonado, Rafael; Dierssen, Mara

    2010-01-01

    Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met(5)-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

  4. Increased opioid dependence in a mouse model of panic disorder

    Directory of Open Access Journals (Sweden)

    Xavier Gallego

    2010-02-01

    Full Text Available Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3. Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 locus coeruleus neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in locus coeruleus and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

  5. The Sound of Silence: Mouse Models for Hearing Loss

    Directory of Open Access Journals (Sweden)

    Sumantra Chatterjee

    2011-01-01

    Full Text Available Sensorineural hearing loss is one of the most common disabilities in humans. It is estimated that about 278 million people worldwide have slight to extreme hearing loss in both ears, which results in an economic loss for the country and personal loss for the individual. It is thus critical to have a deeper understanding of the causes for hearing loss to better manage and treat the affected individuals. The mouse serves as an excellent model to study and recapitulate some of these phenotypes, identify new genes which cause deafness, and to study their roles in vivo and in detail. Mutant mice have been instrumental in elucidating the function and mechanisms of the inner ear. The development and morphogenesis of the inner ear from an ectodermal layer into distinct auditory and vestibular components depends on well-coordinated gene expression and well-orchestrated signaling cascades within the otic vesicle and interactions with surrounding layers of tissues. Any disruption in these pathways can lead to hearing impairment. This review takes a look at some of the genes and their corresponding mice mutants that have shed light on the mechanism governing hearing impairment (HI in humans.

  6. Cannabinoids attenuate cancer pain and proliferation in a mouse model.

    Science.gov (United States)

    Saghafi, Negin; Lam, David K; Schmidt, Brian L

    2011-01-25

    We investigated the effects of cannabinoid receptor agonists on (1) oral cancer cell viability in vitro and (2) oral cancer pain and tumor growth in a mouse cancer model. We utilized immunohistochemistry and Western blot to show that human oral cancer cells express CBr1 and CBr2. When treated with WIN55,212-2 (non-selective), ACEA (CBr1-selective) or AM1241 (CBr2-selective) agonists in vitro, oral cancer cell proliferation was significantly attenuated in a dose-dependent manner. In vivo, systemic administration (0.013M) of WIN55,212-2, ACEA, or AM1241 significantly attenuated cancer-induced mechanical allodynia. Tumor growth was also significantly attenuated with systemic AM1241 administration. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  7. Multimodal nonlinear optical imaging of cartilage development in mouse model

    Science.gov (United States)

    He, Sicong; Xue, Wenqian; Sun, Qiqi; Li, Xuesong; Huang, Jiandong; Qu, Jianan Y.

    2017-02-01

    Kinesin-1 is a kind of motor protein responsible for intracellular transportation and has been studied in a variety of tissues. However, its roles in cartilage development are not clear. In this study, a kinesin-1 heavy chain (Kif5b) knockout mouse model is used to study the functions of kinesin-1 in the cartilage development. We developed a multimodal nonlinear optical (NLO) microscope system integrating stimulated Raman scattering (SRS), second harmonic generation (SHG) and two-photon excited fluorescence (TPEF) to investigate the morphological and biomedical characteristics of fresh tibial cartilage from normal and mutant mice at different developmental stages. The combined forward and backward SHG imaging resolved the fine structure of collagen fibrils in the extracellular matrix of cartilage. Meanwhile, the chondrocyte morphology in different zones of cartilage was visualized by label-free SRS and TPEF images. The results show that the fibrillar collagen in the superficial zone of cartilage in postnatal day 10 and 15 (P10 and P15) knockout mice was significantly less than that of control mice. Moreover, we observed distorted morphology and disorganization of columnar arrangement of chondrocytes in the growth plate cartilage of mutant mice. This study reveals the significant roles of kinesin-1 in collagen formation and chondrocyte morphogenesis.

  8. RANKL, osteopontin, and osteoclast homeostasis in a hyperocclusion mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Cameron G.; Ito, Yoshihiro; Dangaria, Smit; Luan, Xianghong; Diekwisch, Thomas G.H. (UIC)

    2009-10-21

    The biological mechanisms that maintain the position of teeth in their sockets establish a dynamic equilibrium between bone resorption and apposition. In order to reveal some of the dynamics involved in the tissue responses towards occlusal forces on periodontal ligament (PDL) and alveolar bone homeostasis, we developed the first mouse model of hyperocclusion. Swiss-Webster mice were kept in hyperocclusion for 0, 3, 6, and 9 d. Morphological and histological changes in the periodontium were assessed using micro-computed tomography (micro-CT) and ground sections with fluorescent detection of vital dye labels. Sections were stained for tartrate-resistant acid phosphatase, and the expression of receptor activator of nuclear factor-{kappa}B ligand (RANKL) and osteopontin (OPN) was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). Traumatic occlusion resulted in enamel surface abrasion, inhibition of alveolar bone apposition, significant formation of osteoclasts at 3, 6 and 9 d, and upregulation of OPN and RANKL. Data from this study suggest that both OPN and RANKL contribute to the stimulation of bone resorption in the hyperocclusive state. In addition, we propose that the inhibition of alveolar bone apposition by occlusal forces is an important mechanism for the control of occlusal height that might work in synergy with RANKL-induced bone resorption to maintain normal occlusion.

  9. Mouse ES cell culture system as a model of development.

    Science.gov (United States)

    Niwa, Hitoshi

    2010-04-01

    Mouse embryonic stem (mES) cells are pluripotent stem cells derived from pre-implantation embryos. They are regarded as an essential tool for studying mouse development, as they provide a means for generating knock-out mouse lines. This, however, is not the sole utility of the mES cell system. They undergo differentiation in culture, mimicking the morphological differentiation of peri-implantation embryos from epiblast to egg-cylinder stage. Moreover, they retain the capacity to respond to triggers of differentiation toward trophectoderm and primitive endoderm by forced activation. For these reasons, mES cells can be regarded as a useful tool for analyzing molecular mechanisms underlying early mouse development.

  10. A gastrointestinal rotavirus infection mouse model for immune modulation studies

    Directory of Open Access Journals (Sweden)

    van Amerongen Geert

    2011-03-01

    Full Text Available Abstract Background Rotaviruses are the single most important cause of severe diarrhea in young children worldwide. The current study was conducted to assess whether colostrum containing rotavirus-specific antibodies (Gastrogard-R® could protect against rotavirus infection. In addition, this illness model was used to study modulatory effects of intervention on several immune parameters after re-infection. Methods BALB/c mice were treated by gavage once daily with Gastrogard-R® from the age of 4 to 10 days, and were inoculated with rhesus rotavirus (RRV at 7 days of age. A secondary inoculation with epizootic-diarrhea infant-mouse (EDIM virus was administered at 17 days of age. Disease symptoms were scored daily and viral shedding was measured in fecal samples during the post-inoculation periods. Rotavirus-specific IgM, IgG and IgG subclasses in serum, T cell proliferation and rotavirus-specific delayed-type hypersensitivity (DTH responses were also measured. Results Primary inoculation with RRV induced a mild but consistent level of diarrhea during 3-4 days post-inoculation. All mice receiving Gastrogard-R® were 100% protected against rotavirus-induced diarrhea. Mice receiving both RRV and EDIM inoculation had a lower faecal-viral load following EDIM inoculation then mice receiving EDIM alone or Gastrogard-R®. Mice receiving Gastrogard-R® however displayed an enhanced rotavirus-specific T-cell proliferation whereas rotavirus-specific antibody subtypes were not affected. Conclusions Preventing RRV-induced diarrhea by Gastrogard-R® early in life showed a diminished protection against EDIM re-infection, but a rotavirus-specific immune response was developed including both B cell and T cell responses. In general, this intervention model can be used for studying clinical symptoms as well as the immune responses required for protection against viral re-infection.

  11. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome

    National Research Council Canada - National Science Library

    Osterweil, Emily K; Chuang, Shih-Chieh; Chubykin, Alexander A; Sidorov, Michael; Bianchi, Riccardo; Wong, Robert K S; Bear, Mark F

    2013-01-01

    .... We discovered that lovastatin, a drug that is widely prescribed for the treatment of high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent one...

  12. A new conditional Apc-mutant mouse model for colorectal cancer

    NARCIS (Netherlands)

    E.C. Robanus-Maandag (Els); P.J. Koelink (Pim); C. Breukel (Cor); D.C.F. Salvatori (Daniela); S.C. Jagmohan-Changur (Shantie); C.A.J. Bosch (Cathy); H.W. Verspaget; P. Devilee (Peter); R. Fodde (Riccardo); M.J.M. Smits (Ron)

    2010-01-01

    textabstractMutations of the adenomatous polyposis coli (APC) gene predispose individuals to familial adenomatous polyposis (FAP), characterized by multiple tumours in the large intestine. Most mouse models heterozygous for truncating mutant Apc alleles mimic FAP, however, the intestinal tumours

  13. Inhibition of Dermatophilus congolensis infection in a mouse model by antibiotic-producing staphylococci.

    OpenAIRE

    Noble, W. C.; Lloyd, D. H.; Appiah, S. N.

    1980-01-01

    In an acute model of skin infection with Dermatophilus congolensis in the mouse, lesions can be prevented by simultaneous application of staphylococci which produce antibiotics; non-producer staphylococci fail to inhibit lesion formation.

  14. Inhibition of Dermatophilus congolensis infection in a mouse model by antibiotic-producing staphylococci.

    Science.gov (United States)

    Noble, W C; Lloyd, D H; Appiah, S N

    1980-12-01

    In an acute model of skin infection with Dermatophilus congolensis in the mouse, lesions can be prevented by simultaneous application of staphylococci which produce antibiotics; non-producer staphylococci fail to inhibit lesion formation.

  15. Rifalazil and derivative compounds show potent efficacy in a mouse model of H. pylori colonization.

    Science.gov (United States)

    Rothstein, David M; Mullin, Steve; Sirokman, Klari; Söndergaard, Karen L; Johnson, Starrla; Gwathmey, Judith K; van Duzer, John; Murphy, Christopher K

    2008-08-01

    The rifamycin rifalazil (RFZ), and derivatives (NCEs) were efficacious in a mouse model of Helicobacter pylori colonization. Select NCEs were more active in vitro and showed greater efficacy than RFZ. A systemic component contributes to efficacy.

  16. Mouse Model of Human Breast Cancer Initiated by a Fusion Oncogene

    National Research Council Canada - National Science Library

    Orkin, Stuart H

    2006-01-01

    In this study, we generated a novel mouse model of human breast cancer based on a recurrent chromosomal translocation that produces the TEL-NTRK3 fusion oncogene, as the initiating mutation in human...

  17. Alterations in nuclear structure promote lupus autoimmunity in a mouse model

    National Research Council Canada - National Science Library

    Singh, Namrata; Johnstone, Duncan B; Martin, Kayla A; Tempera, Italo; Kaplan, Mariana J; Denny, Michael F

    2016-01-01

    ... the nuclear membrane protein lamin B receptor (LBR), consistent with their Pelger-Huet-like nuclear morphology, we used a novel mouse model system to test the hypothesis that a disruption in the structure of the nucleus itself also contributes...

  18. Novel autoimmune response in a tauopathy mouse model

    Directory of Open Access Journals (Sweden)

    Carlos J Nogueras-Ortiz

    2014-01-01

    Full Text Available Molecular diagnostic tools with non-invasive properties that allow detection of pathological events in Alzheimer’s disease (AD and other neurodegenerative tauopathies are essential for the development of therapeutics. Several diagnostic strategies based on the identification of biomarkers have been proposed. However, its specificity among neurodegenerative disorders is disputable as the association with pathological events remains elusive. Recently, we showed that Amphiphysin-1 (AMPH1 protein’s abundance is reduced in the central nervous system (CNS of the tauopathy mouse model JNPL3 and AD brains. AMPH1 is a synaptic protein that plays an important role in clathrin-mediated endocytosis and associates with BIN1, one of the most important risk loci for AD. Also, it has been associated with a rare neurological disease known as Stiff-Person Syndrome (SPS. Auto-antibodies against AMPH1 are used as diagnostic biomarkers for a paraneoplastic variant of SPS. Therefore, we set up to evaluate the presence and abundance of auto-AMPH1 antibodies in tau-mediated neurodegeneration. Immunoblots and enzyme-linked immunosorbent assays (ELISA were conducted to detect the presence of auto-AMPH1 antibodies in sera from euthanized mice that developed neurodegeneration (JNPL3 and healthy control mice (NTg. Results showed increased levels of auto-AMPH1 antibodies in JNPL3 sera compared to NTg controls. The abundance of auto-AMPH1 antibodies correlated with motor impairment and AMPH1 protein level decrease in the CNS. The results suggest that auto-AMPH1 antibodies could serve as a biomarker for the progression of tau-mediated neurodegeneration in JNPL3 mice.

  19. Metabolic phenotype in the mouse model of osteogenesis imperfecta.

    Science.gov (United States)

    Boraschi-Diaz, Iris; Tauer, Josephine T; El-Rifai, Omar; Guillemette, Delphine; Lefebvre, Geneviève; Rauch, Frank; Ferron, Mathieu; Komarova, Svetlana V

    2017-09-01

    Osteogenesis imperfecta (OI) is the most common heritable bone fragility disorder, usually caused by dominant mutations in genes coding for collagen type I alpha chains, COL1A1 or COL1A2 Osteocalcin (OCN) is now recognized as a bone-derived regulator of insulin secretion and sensitivity and glucose homeostasis. Since OI is associated with increased rates of bone formation and resorption, we hypothesized that the levels of undercarboxylated OCN are increased in OI. The objective of this study was to determine changes in OCN and to elucidate the metabolic phenotype in the Col1a1 Jrt/+ mouse, a model of dominant OI caused by a Col1a1 mutation. Circulating levels of undercarboxylated OCN were higher in 4-week-old OI mice and normal by 8 weeks of age. Young OI animals exhibited a sex-dependent metabolic phenotype, including increased insulin levels in males, improved glucose tolerance in females, lower levels of random glucose and low adiposity in both sexes. The rates of O 2 consumption and CO 2 production, as well as energy expenditure assessed using indirect calorimetry were significantly increased in OI animals of both sexes, whereas respiratory exchange ratio was significantly higher in OI males only. Although OI mice have significant physical impairment that may contribute to metabolic differences, we specifically accounted for movement and compared OI and WT animals during the periods of similar activity levels. Taken together, our data strongly suggest that OI animals have alterations in whole body energy metabolism that are consistent with the action of undercarboxylated osteocalcin. © 2017 Society for Endocrinology.

  20. A Mouse Model to Investigate Postmenopausal Biology as an Etiology of Ovarian Cancer Risk

    Science.gov (United States)

    2009-11-01

    We investigated the potential use of genetically engineered Vesicular Stomatitis Virus ( VSV ) to treat ovarian cancer using the Wv mouse models. We...l e i n f oArticle history: Received 2 September 2009 Available online x Keywords: Ovarian Cancer Therapy Oncolytic virus VSV Tumor mouse models...cancer is an urgent agenda. We investigated the potential use of genetically engineered Vesicular Stomatitis Virus ( VSV ) to treat ovarian cancer patients

  1. Disease Heterogeneity and Immune Biomarkers in Preclinical Mouse Models of Ovarian Carcinogenesis

    Science.gov (United States)

    2015-10-01

    1 Award Number: W81XWH-10-1-0525 TITLE: Disease Heterogeneity and Immune Biomarkers in Preclinical Mouse Models of Ovarian Carcinogenesis...Disease Heterogeneity and Immune Biomarkers in Preclinical Mouse Models of Ovarian Carcinogenesis Magee Womens Research Institute 204 Craft Ave...KrasPten mice Aim 2: To profile disease heterogeneity and to identify immune biomarkers of natural and vaccine-induced immune responses in mice with

  2. Regulatory Forum commentary: alternative mouse models for future cancer risk assessment.

    Science.gov (United States)

    Morton, Daniel; Sistare, Frank D; Nambiar, Prashant R; Turner, Oliver C; Radi, Zaher; Bower, Nancy

    2014-07-01

    International regulatory and pharmaceutical industry scientists are discussing revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S1 guidance on rodent carcinogenicity assessment of small molecule pharmaceuticals. A weight-of-evidence approach is proposed to determine the need for rodent carcinogenicity studies. For compounds with high human cancer risk, the product may be labeled appropriately without conducting rodent carcinogenicity studies. For compounds with minimal cancer risk, only a 6-month transgenic mouse study (rasH2 mouse or p53+/- mouse) or a 2-year mouse study would be needed. If rodent carcinogenicity testing may add significant value to cancer risk assessment, a 2-year rat study and either a 6-month transgenic mouse or a 2-year mouse study is appropriate. In many cases, therefore, one rodent carcinogenicity study could be sufficient. The rasH2 model predicts neoplastic findings relevant to human cancer risk assessment as well as 2-year rodent models, produces fewer irrelevant neoplastic outcomes, and often will be preferable to a 2-year rodent study. Before revising ICH S1 guidance, a prospective evaluation will be conducted to test the proposed weight-of-evidence approach. This evaluation offers an opportunity for a secondary analysis comparing the value of alternative mouse models and 2-year rodent studies in the proposed ICH S1 weight-of-evidence approach for human cancer risk assessment. © 2014 by The Author(s).

  3. A mouse model for binge-level methamphetamine use

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    Shkelzen Shabani

    2016-11-01

    Full Text Available Binge/crash cycles of methamphetamine (MA use are frequently reported by individuals suffering from MA use disorders. An MA binge is self-reported as multiple daily doses that commonly accumulate to 800 mg/day (~10 mg/kg/day for a 170 pound human. A genetic animal model with a similar vulnerability to binge-level MA intake is missing. We used selectively bred MA high drinking (MAHDR and low drinking (MALDR mouse lines to determine whether several procedural variations would result in binge-level MA intake. Data were also collected in two progenitor populations of the MA drinking lines, the DBA/2J (D2 strain and the F2 cross of the D2 and C57BL/6J strains. The impact of 3 factors was examined: (1 concentration of MA in the two-bottle choice procedure used for selective breeding; (2 ratio of bottles containing MA vs. water, and (3 length of the withdrawal (or abstinence period between MA drinking sessions. When MA concentration was progressively increased every 4 days in 20 mg/l amounts from 20 to 140 mg/l, maximum intake in MALDR mice was 1.1 mg/kg, whereas MAHDR mice consumed as much as 14.6 mg/kg. When these concentrations were tested in a multiple bottle choice procedure, the highest ratio of MA to water bottles (3:1 was associated with escalated MA intake of up to 29.1 mg/kg in MAHDR mice and 12.0 mg/kg in F2 mice; MALDR mice did not show a ratio-dependent escalation in MA intake. Finally, MAHDR and D2 mice were offered 3 bottles of MA vs. water at increasing concentrations from 20 to 80 mg/l, and tested under an intermittent 6-h withdrawal period, which was lengthened to 30 hours (D2 mice or to 30 or 78 hours (MAHDR. D2 and MAHDR mice initially consumed similar amounts of 14-16 mg/kg MA, but D2 mice reduced their MA intake 3-fold after introduction of 30-h abstinence periods, whereas MAHDR mice retained their high level of intake regardless of withdrawal period. MAHDR mice provide a genetic model of binge-level MA intake appropriate for the

  4. The Effects of Genetic Background of Mouse Models of Cancer: Friend or Foe?

    Science.gov (United States)

    Reilly, Karlyne M

    2016-03-01

    Over the past century, mice have been selectively bred to give rise to the strains used in biomedical research today. Mouse models of cancer allow researchers to control variables of diet, environment, and genetic heterogeneity to better dissect the role of these factors in cancer in humans. Because of the important role of genetic background in cancer, the strain of the mouse can introduce confounding results in studies of mouse models if not properly controlled. Conversely, genetic variation between strains can also provide important new insights into cancer mechanisms. Here, the sources of genetic heterogeneity in mouse models are reviewed, with an explanation of how heterogeneity modifies cancer phenotypes. © 2016 Cold Spring Harbor Laboratory Press.

  5. A novel mouse xenotransplantation model of EBV-T/NK-LPD and the application of the mouse model.

    Science.gov (United States)

    Imadome, Ken-Ichi

    2013-01-01

    Chronic active Epstein-Barr virus (EBV) infection (CAEBV), characterized by proliferation of EBV-infected T or NK cells, is a disease of unknown pathogenesis and requires hematopoietic stem cell transplantation for curative treatment. Here we show that intravenous injection of peripheral blood mononuclear cells (PBMCs) isolated from patients with CAEBV to NOD/Shi-scid/IL-2R γ(null) (NOG) mice leads to engraftment of EBV-infected T or NK cells. Analysis of TCR repertoire identified an identical predominant EBV-infected T-cell clone both in a patient and a mouse transplanted with his PBMCs. EBV-infected T or NK cells infiltrated to most major organs including the liver, spleen, lungs, kidneys, adrenal glands, and intestine, showing histological characteristics of CAEBV. Expression of EBNA1, LMP1, and LMP2A, but not EBNA2, in these cells indicated the latency II program of EBV gene characteristic to CAEBV. High levels of TNF-α, IFN-γ, and RANTES were detected in the peripheral blood of these mice. EBV-containing fractions of either CD8(+), γδT, or NK cell lineages failed to engraft, once they were isolated from PBMCs ; they could engraft only when CD4(+) cell fraction was transplanted in parallel. Isolated EBV-containing CD4(+) T cells, in contrast, did engraft on their own. This is the first report of an animal model of CAEBV and suggest that EBV-infected T or NK cells in CAEBV are not truly neoplastic but are dependent on CD4(+) T cells for their proliferation in vivo.

  6. A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse.

    Science.gov (United States)

    Nalbandian, Angèle; Llewellyn, Katrina J; Badadani, Mallikarjun; Yin, Hong Z; Nguyen, Christopher; Katheria, Veeral; Watts, Giles; Mukherjee, Jogeshwar; Vesa, Jouni; Caiozzo, Vincent; Mozaffar, Tahseen; Weiss, John H; Kimonis, Virginia E

    2013-02-01

    Mutations in the valosin-containing protein (VCP) gene cause hereditary inclusion body myopathy (IBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently, these mutations have been linked to 2% of familial amyotrophic lateral sclerosis (ALS) cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis. The VCP(R155H/+) knock-in mouse model was assessed for muscle strength and immunohistochemical, Western blot, apoptosis, autophagy, and microPET/CT imaging analyses. VCP(R155H/+) mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies, and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons. VCP(R155H/+) knock-in mice represent an excellent preclinical model for understanding VCP-associated disease mechanisms and future treatments. Copyright © 2012 Wiley Periodicals, Inc.

  7. The mouse as a model for human biology: a resource guide for complex trait analysis.

    Science.gov (United States)

    Peters, Luanne L; Robledo, Raymond F; Bult, Carol J; Churchill, Gary A; Paigen, Beverly J; Svenson, Karen L

    2007-01-01

    The mouse has been a powerful force in elucidating the genetic basis of human physiology and pathophysiology. From its beginnings as the model organism for cancer research and transplantation biology to the present, when dissection of the genetic basis of complex disease is at the forefront of genomics research, an enormous and remarkable mouse resource infrastructure has accumulated. This review summarizes those resources and provides practical guidelines for their use, particularly in the analysis of quantitative traits.

  8. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease.

    Science.gov (United States)

    Agrawal, Anurodh Shankar; Garron, Tania; Tao, Xinrong; Peng, Bi-Hung; Wakamiya, Maki; Chan, Teh-Sheng; Couch, Robert B; Tseng, Chien-Te K

    2015-04-01

    The emergence of Middle East respiratory syndrome-coronavirus (MERS-CoV) in the Middle East since 2012 has caused more than 900 human infections with ∼40% mortality to date. Animal models are needed for studying pathogenesis and for development of preventive and therapeutic agents against MERS-CoV infection. Nonhuman primates (rhesus macaques and marmosets) are expensive models of limited availability. Although a mouse lung infection model has been described using adenovirus vectors expressing human CD26/dipeptidyl peptidase 4 (DPP4), it is believed that a transgenic mouse model is needed for MERS-CoV research. We have developed this transgenic mouse model as indicated in this study. We show that transgenic mice globally expressing hCD26/DPP4 were fully permissive to MERS-CoV infection, resulting in relentless weight loss and death within days postinfection. High infectious virus titers were recovered primarily from the lungs and brains of mice at 2 and 4 days postinfection, respectively, whereas viral RNAs were also detected in the heart, spleen, and intestine, indicating a disseminating viral infection. Infected Tg(+) mice developed a progressive pneumonia, characterized by extensive inflammatory infiltration. In contrast, an inconsistent mild perivascular cuffing was the only pathological change associated with the infected brains. Moreover, infected Tg(+) mice were able to activate genes encoding for many antiviral and inflammatory mediators within the lungs and brains, coinciding with the high levels of viral replication. This new and unique transgenic mouse model will be useful for furthering knowledge of MERS pathogenesis and for the development of vaccine and treatments against MERS-CoV infection. Small and economical animal models are required for the controlled and extensive studies needed for elucidating pathogenesis and development of vaccines and antivirals against MERS. Mice are the most desirable small-animal species for this purpose because of

  9. Histopathological characteristics of a novel knock-in mouse prostate cancer model

    Directory of Open Access Journals (Sweden)

    G. Wu

    2006-06-01

    Full Text Available Prostate cancer is relatively unique to man. There is no naturally occurring prostate cancer in the mouse. Pre-clinical studies involve the establishment of a genetically engineered mouse prostate cancer model with features close to those of the human situation. A new knock-in mouse adenocarcinoma prostate (KIMAP model was established, which showed close-to-human kinetics of tumor development. In order to determine if the similar kinetics is associated with heterogeneous tumor architecture similar to the human situation, we utilized a new mouse histological grading system (Gleason analogous grading system similar to the Gleason human grading system and flow cytometry DNA analysis to measure and compare the adenocarcinoma of the KIMAP model with human prostate cancer. Sixty KIMAP prostate cancer samples from 60 mice were measured and compared with human prostate cancer. Flow cytometry DNA analysis was performed on malignant prostate tissues obtained from KIMAP models. Mice with prostate cancer from KIMAP models showed a 53.3% compound histological score rate, which was close to the human clinical average (50% and showed a significant correlation with age (P = 0.001. Flow cytometry analyses demonstrated that most KIMAP tumor tissues were diploid, analogous to the human situation. The similarities of the KIMAP mouse model with tumors of the human prostate suggest the use of this experimental model to complement studies of human prostate cancer.

  10. A progressive translational mouse model of human valosin-containing protein disease: The VCPR155H/+ mouse

    OpenAIRE

    Nalbandian, A; Llewellyn, KJ; Badadani, M; Yin, HZ; Nguyen, C; Katheria, V; G. Watts; Mukherjee, J.; Vesa, J; Caiozzo, V; Mozaffar, T. (Tahseen); Weiss, JH; Kimonis, VE

    2013-01-01

    Introduction: Mutations in the valosin-containing protein (VCP) gene cause hereditary inclusion body myopathy (IBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently, these mutations have been linked to 2% of familial amyotrophic lateral sclerosis (ALS) cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis. Methods: The VCP R155H/+ knock-in mouse model was assessed for muscle strength and immunohistochemical, Wes...

  11. Defining the role of polyamines in colon carcinogenesis using mouse models

    Directory of Open Access Journals (Sweden)

    Natalia A Ignatenko

    2011-01-01

    Full Text Available Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention.

  12. A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains.

    Science.gov (United States)

    Sankoorikal, Geena Mary V; Kaercher, Kristin A; Boon, Catherine J; Lee, Jin Kyoung; Brodkin, Edward S

    2006-03-01

    Impairments in social behaviors are highly disabling symptoms of autism, schizophrenia, and other psychiatric disorders. Mouse model systems are useful for identifying the many genes and environmental factors likely to affect complex behaviors, such as sociability (the tendency to seek social interaction). To progress toward developing such a model system, we tested the hypothesis that C57BL/6J inbred mice show higher levels of sociability than BALB/cJ inbred mice. Mice tested for sociability were 4- and 9-week-old, male and female C57BL/6J and BALB/cJ mice. On 2 consecutive days, the sociability of each test mouse toward an unfamiliar 4-week-old DBA/2J stimulus mouse was assessed with a social choice paradigm conducted in a three-chambered apparatus. Measures of sociability included the time that the test mouse spent near versus far from the stimulus mouse, the time spent directly sniffing the stimulus mouse, and the time spent in contact between test and stimulus mice in a free interaction. C57BL/6J mice showed higher levels of sociability than BALB/cJ mice overall in each of these measures. We propose that C57BL/6J and BALB/cJ mice will be a useful mouse model system for future genetic and neurobiological studies of sociability.

  13. Common circuit defect of excitatory-inhibitory balance in mouse models of autism.

    Science.gov (United States)

    Gogolla, Nadine; Leblanc, Jocelyn J; Quast, Kathleen B; Südhof, Thomas C; Fagiolini, Michela; Hensch, Takao K

    2009-06-01

    One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/inhibitory (E/I) circuit balance during critical periods of development. We examined whether Parvalbumin (PV)-positive inhibitory neurons, which normally drive experience-dependent circuit refinement (Hensch Nat Rev Neurosci 6:877-888, 1), are disrupted across heterogeneous ASD mouse models. We performed a meta-analysis of PV expression in previously published ASD mouse models and analyzed two additional models, reflecting an embryonic chemical insult (prenatal valproate, VPA) or single-gene mutation identified in human patients (Neuroligin-3, NL-3 R451C). PV-cells were reduced in the neocortex across multiple ASD mouse models. In striking contrast to controls, both VPA and NL-3 mouse models exhibited an asymmetric PV-cell reduction across hemispheres in parietal and occipital cortices (but not the underlying area CA1). ASD mouse models may share a PV-circuit disruption, providing new insight into circuit development and potential prevention by treatment of autism. The online version of this article (doi:10.1007/s11689-009-9023-x) contains supplementary material, which is available to authorized users.

  14. A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses

    Energy Technology Data Exchange (ETDEWEB)

    Salek, Reza M.; Pears, Michael R. [University of Cambridge, Department of Biochemistry and Cambridge Systems Biology Centre (United Kingdom); Cooper, Jonathan D. [King' s College London, Pediatric Storage Disorders Laboratory, Department of Neuroscience, Institute of Psychiatry (United Kingdom); Mitchison, Hannah M. [Royal Free and University College Medical School, Department of Paediatrics and Child Health (United Kingdom); Pearce, David A. [Sanford School of Medicine of the University of South Dakota, Department of Pediatrics (United States); Mortishire-Smith, Russell J. [Johnson and Johnson PR and D (Belgium); Griffin, Julian L., E-mail: jlg40@mole.bio.cam.ac.uk [University of Cambridge, Department of Biochemistry and the Cambridge Systems Biology Centre (United Kingdom)

    2011-04-15

    The Neuronal Ceroid Lipofuscinoses (NCL) are a group of fatal inherited neurodegenerative diseases in humans distinguished by a common clinical pathology, characterized by the accumulation of storage body material in cells and gross brain atrophy. In this study, metabolic changes in three NCL mouse models were examined looking for pathways correlated with neurodegeneration. Two mouse models; motor neuron degeneration (mnd) mouse and a variant model of late infantile NCL, termed the neuronal ceroid lipofuscinosis (nclf) mouse were investigated experimentally. Both models exhibit a characteristic accumulation of autofluorescent lipopigment in neuronal and non neuronal cells. The NMR profiles derived from extracts of the cortex and cerebellum from mnd and nclf mice were distinguished according to disease/wildtype status. In particular, a perturbation in glutamine and glutamate metabolism, and a decrease in {gamma}-amino butyric acid (GABA) in the cerebellum and cortices of mnd (adolescent mice) and nclf mice relative to wildtype at all ages were detected. Our results were compared to the Cln3 mouse model of NCL. The metabolism of mnd mice resembled older (6 month) Cln3 mice, where the disease is relatively advanced, while the metabolism of nclf mice was more akin to younger (1-2 months) Cln3 mice, where the disease is in its early stages of progression. Overall, our results allowed the identification of metabolic traits common to all NCL subtypes for the three animal models.

  15. Alterations in Striatal Synaptic Transmission are Consistent across Genetic Mouse Models of Huntington's Disease

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    Damian M Cummings

    2010-05-01

    Full Text Available Since the identification of the gene responsible for HD (Huntington's disease, many genetic mouse models have been generated. Each employs a unique approach for delivery of the mutated gene and has a different CAG repeat length and background strain. The resultant diversity in the genetic context and phenotypes of these models has led to extensive debate regarding the relevance of each model to the human disorder. Here, we compare and contrast the striatal synaptic phenotypes of two models of HD, namely the YAC128 mouse, which carries the full-length huntingtin gene on a yeast artificial chromosome, and the CAG140 KI*** (knock-in mouse, which carries a human/mouse chimaeric gene that is expressed in the context of the mouse genome, with our previously published data obtained from the R6/2 mouse, which is transgenic for exon 1 mutant huntingtin. We show that striatal MSNs (medium-sized spiny neurons in YAC128 and CAG140 KI mice have similar electrophysiological phenotypes to that of the R6/2 mouse. These include a progressive increase in membrane input resistance, a reduction in membrane capacitance, a lower frequency of spontaneous excitatory postsynaptic currents and a greater frequency of spontaneous inhibitory postsynaptic currents in a subpopulation of striatal neurons. Thus, despite differences in the context of the inserted gene between these three models of HD, the primary electrophysiological changes observed in striatal MSNs are consistent. The outcomes suggest that the changes are due to the expression of mutant huntingtin and such alterations can be extended to the human condition.

  16. Olfaction in three genetic and two MPTP-induced Parkinson's disease mouse models.

    Directory of Open Access Journals (Sweden)

    Stefan Kurtenbach

    Full Text Available Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson's disease (PD mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs and an olfactory behavior test (cookie-finding test. We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated α-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated α-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium.

  17. Ultrastructural study of Rift Valley fever virus in the mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Reed, Christopher; Steele, Keith E.; Honko, Anna; Shamblin, Joshua; Hensley, Lisa E. [United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD (United States); Smith, Darci R., E-mail: darci.smith1@us.army.mil [United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD (United States)

    2012-09-15

    Detailed ultrastructural studies of Rift Valley fever virus (RVFV) in the mouse model are needed to develop and characterize a small animal model of RVF for the evaluation of potential vaccines and therapeutics. In this study, the ultrastructural features of RVFV infection in the mouse model were analyzed. The main changes in the liver included the presence of viral particles in hepatocytes and hepatic stem cells accompanied by hepatocyte apoptosis. However, viral particles were observed rarely in the liver; in contrast, particles were extremely abundant in the CNS. Despite extensive lymphocytolysis, direct evidence of viral replication was not observed in the lymphoid tissue. These results correlate with the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF, but suggest that host immune-mediated mechanisms contribute significantly to pathology. The results of this study expand our knowledge of RVFV-host interactions and further characterize the mouse model of RVF.

  18. A Multihit Model: Colitis Lessons from the Interleukin-10–deficient Mouse

    Science.gov (United States)

    Keubler, Lydia M.; Buettner, Manuela; Häger, Christine

    2015-01-01

    Abstract: Complex mechanisms are pulling the strings to initiate the development of inflammatory bowel disease. Current evidence indicates that an interaction of genetic susceptibilities (polymorphisms), environmental factors, and the host microbiota leads to a dysregulation of the mucosal immune system. In the past decades, the interleukin-10–deficient mouse has served as an excellent model to mirror the multifactorial nature of this disease. Here, we want to review in detail the interplay of the genetic factors, immune aspects, and especially summarize and discuss the role of the microbiota contributing to colitis development in the interleukin-10–deficient mouse model of inflammatory bowel disease as a multihit model. PMID:26164667

  19. Analysis of TMEFF2 allografts and transgenic mouse models reveals roles in prostate regeneration and cancer.

    Science.gov (United States)

    Corbin, Joshua M; Overcash, Ryan F; Wren, Jonathan D; Coburn, Anita; Tipton, Greg J; Ezzell, Jennifer A; McNaughton, Kirk K; Fung, Kar-Ming; Kosanke, Stanley D; Ruiz-Echevarria, Maria J

    2016-01-01

    Previous results from our lab indicate a tumor suppressor role for the transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) in prostate cancer (PCa). Here, we further characterize this role and uncover new functions for TMEFF2 in cancer and adult prostate regeneration. The role of TMEFF2 was examined in PCa cells using Matrigel(TM) cultures and allograft models of PCa cells. In addition, we developed a transgenic mouse model that expresses TMEFF2 from a prostate specific promoter. Anatomical, histological, and metabolic characterizations of the transgenic mouse prostate were conducted. The effect of TMEFF2 in prostate regeneration was studied by analyzing branching morphogenesis in the TMEFF2-expressing mouse lobes and alterations in branching morphogenesis were correlated with the metabolomic profiles of the mouse lobes. The role of TMEFF2 in prostate tumorigenesis in whole animals was investigated by crossing the TMEFF2 transgenic mice with the TRAMP mouse model of PCa and analyzing the histopathological changes in the progeny. Ectopic expression of TMEFF2 impairs growth of PCa cells in Matrigel or allograft models. Surprisingly, while TMEFF2 expression in the TRAMP mouse did not have a significant effect on the glandular prostate epithelial lesions, the double TRAMP/TMEFF2 transgenic mice displayed an increased incidence of neuroendocrine type tumors. In addition, TMEFF2 promoted increased branching specifically in the dorsal lobe of the prostate suggesting a potential role in developmental processes. These results correlated with data indicating an alteration in the metabolic profile of the dorsal lobe of the transgenic TMEFF2 mice. Collectively, our results confirm the tumor suppressor role of TMEFF2 and suggest that ectopic expression of TMEFF2 in mouse prostate leads to additional lobe-specific effects in prostate regeneration and tumorigenesis. This points to a complex and multifunctional role for TMEFF2 during PCa

  20. Hypothalamic food intake regulation in a cancer-cachectic mouse model

    NARCIS (Netherlands)

    Dwarkasing, J.T.; Dijk, van M.; Dijk, F.J.; Boekschoten, M.V.; Faber, J.; Argiles, J.M.; Laviano, A.; Müller, M.R.; Witkamp, R.F.; Norren, van K.

    2014-01-01

    Background Appetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an

  1. Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 1

    NARCIS (Netherlands)

    Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske

    2013-01-01

    Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have

  2. Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 2

    NARCIS (Netherlands)

    Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske

    2013-01-01

    Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have

  3. Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model

    NARCIS (Netherlands)

    Koopman, F. A.; Vosters, J. L.; Roescher, N.; Broekstra, N.; Tak, P. P.; Vervoordeldonk, M. J.

    2015-01-01

    Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's

  4. Immunocompromised and immunocompetent mouse models for head and neck squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Lei ZG

    2016-01-01

    Full Text Available Zhen-ge Lei,1,* Xiao-hua Ren,2,* Sha-sha Wang,3 Xin-hua Liang,3,4 Ya-ling Tang3,5 1Department of Oral and Maxillofacial Surgery, Stomatological Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 2Department of Stomatology, Sichuan Medical Science Academy and Sichuan Provincial People’s Hospital, 3State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, 4Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, 5Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China *These authors contributed equally to this work Abstract: Mouse models can closely mimic human oral squamous epithelial carcinogenesis, greatly expand the in vivo research possibilities, and play a critical role in the development of diagnosis, monitoring, and treatment of head and neck squamous cell carcinoma. With the development of the recent research on the contribution of immunity/inflammation to cancer initiation and progression, mouse models have been divided into two categories, namely, immunocompromised and immunocompetent mouse models. And thus, this paper will review these two kinds of models applied in head and neck squamous cell carcinoma to provide a platform to understand the complicated histological, molecular, and genetic changes of oral squamous epithelial tumorigenesis. Keywords: head and neck squamous cell carcinoma, HNSCC, mouse models, immunocompromised models, immunocompetent models, transgenic models

  5. Neuronal mechanisms and circuits underlying repetitive behaviors in mouse models of autism spectrum disorder.

    Science.gov (United States)

    Kim, Hyopil; Lim, Chae-Seok; Kaang, Bong-Kiun

    2016-01-20

    Autism spectrum disorder (ASD) refers to a broad spectrum of neurodevelopmental disorders characterized by three central behavioral symptoms: impaired social interaction, impaired social communication, and restricted and repetitive behaviors. However, the symptoms are heterogeneous among patients and a number of ASD mouse models have been generated containing mutations that mimic the mutations found in human patients with ASD. Each mouse model was found to display a unique set of repetitive behaviors. In this review, we summarize the repetitive behaviors of the ASD mouse models and variations found in their neural mechanisms including molecular and electrophysiological features. We also propose potential neuronal mechanisms underlying these repetitive behaviors, focusing on the role of the cortico-basal ganglia-thalamic circuits and brain regions associated with both social and repetitive behaviors. Further understanding of molecular and circuitry mechanisms of the repetitive behaviors associated with ASD is necessary to aid the development of effective treatments for these disorders.

  6. Distinct Defects in Spine Formation or Pruning in Two Gene Duplication Mouse Models of Autism.

    Science.gov (United States)

    Wang, Miao; Li, Huiping; Takumi, Toru; Qiu, Zilong; Xu, Xiu; Yu, Xiang; Bian, Wen-Jie

    2017-04-01

    Autism spectrum disorder (ASD) encompasses a complex set of developmental neurological disorders, characterized by deficits in social communication and excessive repetitive behaviors. In recent years, ASD is increasingly being considered as a disease of the synapse. One main type of genetic aberration leading to ASD is gene duplication, and several mouse models have been generated mimicking these mutations. Here, we studied the effects of MECP2 duplication and human chromosome 15q11-13 duplication on synaptic development and neural circuit wiring in the mouse sensory cortices. We showed that mice carrying MECP2 duplication had specific defects in spine pruning, while the 15q11-13 duplication mouse model had impaired spine formation. Our results demonstrate that spine pathology varies significantly between autism models and that distinct aspects of neural circuit development may be targeted in different ASD mutations. Our results further underscore the importance of gene dosage in normal development and function of the brain.

  7. Transgenic mouse models for cardiac dysfunction by a specific gene manipulation.

    Science.gov (United States)

    Babu, Gopal J; Periasamy, Muthu

    2005-01-01

    The sarcoplasmic reticulum Ca2+ ATPase (SERCA) plays a pivotal role in calcium cycling and the beat-to-beat function of the heart. Recent studies have shown that decreased expression and activity of SERCA are associated with end-stage heart failure in humans and in experimental animal models of heart failure. There has been considerable controversy over whether a decrease in SERCA level is a cause or effect of hypertrophy. To address directly whether alterations in SERCA levels modify calcium homeostasis and heart function, we have chosen to alter the SERCA protein expression genetically using transgenic and gene-targeted knockout mouse technology. This chapter describes the methodology for generation of mouse models that overexpress different SERCA isoforms and a SERCA2 knockout mouse model with decreased SERCA levels.

  8. The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health.

    Science.gov (United States)

    Ezran, Camille; Karanewsky, Caitlin J; Pendleton, Jozeph L; Sholtz, Alex; Krasnow, Maya R; Willick, Jason; Razafindrakoto, Andriamahery; Zohdy, Sarah; Albertelli, Megan A; Krasnow, Mark A

    2017-06-01

    Systematic genetic studies of a handful of diverse organisms over the past 50 years have transformed our understanding of biology. However, many aspects of primate biology, behavior, and disease are absent or poorly modeled in any of the current genetic model organisms including mice. We surveyed the animal kingdom to find other animals with advantages similar to mice that might better exemplify primate biology, and identified mouse lemurs (Microcebus spp.) as the outstanding candidate. Mouse lemurs are prosimian primates, roughly half the genetic distance between mice and humans. They are the smallest, fastest developing, and among the most prolific and abundant primates in the world, distributed throughout the island of Madagascar, many in separate breeding populations due to habitat destruction. Their physiology, behavior, and phylogeny have been studied for decades in laboratory colonies in Europe and in field studies in Malagasy rainforests, and a high quality reference genome sequence has recently been completed. To initiate a classical genetic approach, we developed a deep phenotyping protocol and have screened hundreds of laboratory and wild mouse lemurs for interesting phenotypes and begun mapping the underlying mutations, in collaboration with leading mouse lemur biologists. We also seek to establish a mouse lemur gene "knockout" library by sequencing the genomes of thousands of mouse lemurs to identify null alleles in most genes from the large pool of natural genetic variants. As part of this effort, we have begun a citizen science project in which students across Madagascar explore the remarkable biology around their schools, including longitudinal studies of the local mouse lemurs. We hope this work spawns a new model organism and cultivates a deep genetic understanding of primate biology and health. We also hope it establishes a new and ethical method of genetics that bridges biological, behavioral, medical, and conservation disciplines, while

  9. The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health

    Science.gov (United States)

    Ezran, Camille; Karanewsky, Caitlin J.; Pendleton, Jozeph L.; Sholtz, Alex; Krasnow, Maya R.; Willick, Jason; Razafindrakoto, Andriamahery; Zohdy, Sarah; Albertelli, Megan A.; Krasnow, Mark A.

    2017-01-01

    Systematic genetic studies of a handful of diverse organisms over the past 50 years have transformed our understanding of biology. However, many aspects of primate biology, behavior, and disease are absent or poorly modeled in any of the current genetic model organisms including mice. We surveyed the animal kingdom to find other animals with advantages similar to mice that might better exemplify primate biology, and identified mouse lemurs (Microcebus spp.) as the outstanding candidate. Mouse lemurs are prosimian primates, roughly half the genetic distance between mice and humans. They are the smallest, fastest developing, and among the most prolific and abundant primates in the world, distributed throughout the island of Madagascar, many in separate breeding populations due to habitat destruction. Their physiology, behavior, and phylogeny have been studied for decades in laboratory colonies in Europe and in field studies in Malagasy rainforests, and a high quality reference genome sequence has recently been completed. To initiate a classical genetic approach, we developed a deep phenotyping protocol and have screened hundreds of laboratory and wild mouse lemurs for interesting phenotypes and begun mapping the underlying mutations, in collaboration with leading mouse lemur biologists. We also seek to establish a mouse lemur gene “knockout” library by sequencing the genomes of thousands of mouse lemurs to identify null alleles in most genes from the large pool of natural genetic variants. As part of this effort, we have begun a citizen science project in which students across Madagascar explore the remarkable biology around their schools, including longitudinal studies of the local mouse lemurs. We hope this work spawns a new model organism and cultivates a deep genetic understanding of primate biology and health. We also hope it establishes a new and ethical method of genetics that bridges biological, behavioral, medical, and conservation disciplines, while

  10. Integrating model behavior, optimization, and sensitivity/uncertainty analysis: overview and application of the MOUSE software toolbox

    Science.gov (United States)

    This paper provides an overview of the Model Optimization, Uncertainty, and SEnsitivity Analysis (MOUSE) software application, an open-source, Java-based toolbox of visual and numerical analysis components for the evaluation of environmental models. MOUSE is based on the OPTAS model calibration syst...

  11. Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Rooney, Jachinta E; Gurpur, Praveen B; Burkin, Dean J

    2009-05-12

    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The alpha(7)beta(1)-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the alpha(7)-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate alpha(7)-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for alpha(7)-integrin expression. We show that laminin-111 (alpha(1), beta(1), gamma(1)), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased alpha(7)-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of alpha(7)-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.

  12. From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis

    Directory of Open Access Journals (Sweden)

    Eléonore Pérès

    2015-12-01

    Full Text Available The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1, is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.

  13. From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis.

    Science.gov (United States)

    Pérès, Eléonore; Bagdassarian, Eugénie; This, Sébastien; Villaudy, Julien; Rigal, Dominique; Gazzolo, Louis; Duc Dodon, Madeleine

    2015-12-07

    The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1), is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.

  14. Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer

    Science.gov (United States)

    2011-02-01

    prostate cancer in a preclinical mouse model. J Clin Invest 118, 3051-3064. 4) Wang, X., Kruithof-de Julio , M., Economides, K. D., Walker, D., Yu, H...Park R, Conti PS, Moats R, Berns A, Shi W, Zhou Z, et al. 2007. Mouse models of prostate adenocarcinoma with the capacity to monitor spontaneous...1779–1786. Ma X, Ziel-van der Made AC, Autar B, van der Korput HA, Vermeij M, van Duijn P, Cleutjens KB, de Krijger R, Krimpenfort P, Berns A, et al

  15. The use of mouse models to understand and improve cognitive deficits in Down syndrome.

    Science.gov (United States)

    Das, Ishita; Reeves, Roger H

    2011-09-01

    Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development.

  16. The use of mouse models to understand and improve cognitive deficits in Down syndrome

    Directory of Open Access Journals (Sweden)

    Ishita Das

    2011-09-01

    Full Text Available Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development.

  17. Evaluation of an in vitro muscle contraction model in mouse primary cultured myotubes.

    Science.gov (United States)

    Manabe, Yasuko; Ogino, Shinya; Ito, Miyuki; Furuichi, Yasuro; Takagi, Mayumi; Yamada, Mio; Goto-Inoue, Naoko; Ono, Yusuke; Fujii, Nobuharu L

    2016-03-15

    To construct an in vitro contraction model with the primary cultured myotubes, we isolated satellite cells from the mouse extensor digitorum longus. Differentiated myotubes possessed a greater number of sarcomere assemblies and higher expression levels of myosin heavy chain, cytochrome c oxidase IV, and myoglobin than in C2C12 myotubes. In agreement with these results regarding the sarcomere assemblies and protein expressions, the primary myotubes showed higher contractile activity stimulated by the electric pulses than that in the C2C12 myotubes. These data suggest that mouse primary myotubes will be a valuable research tool as an in vitro muscle contraction model. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Generating Mouse Models Using Zygote Electroporation of Nucleases (ZEN) Technology with High Efficiency and Throughput.

    Science.gov (United States)

    Wang, Wenbo; Zhang, Yingfan; Wang, Haoyi

    2017-01-01

    Mouse models with genetic modifications are widely used in biology and biomedical research. Although the application of CRISPR-Cas9 system greatly accelerated the process of generating genetically modified mice, the delivery method depending on manual injection of the components into the embryos remains a bottleneck, as it is laborious, low throughput, and technically demanding. To overcome this limitation, we invented and optimized the ZEN (Zygote electroporation of nucleases) technology to deliver CRISPR-Cas9 reagents via electroporation. Using ZEN, we were able to generate genetically modified mouse models with high efficiency and throughput. Here, we describe the protocol in great detail.

  19. Model-Based Tumor Growth Dynamics and Therapy Response in a Mouse Model of De Novo Carcinogenesis.

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    Charalambos Loizides

    Full Text Available Tumorigenesis is a complex, multistep process that depends on numerous alterations within the cell and contribution from the surrounding stroma. The ability to model macroscopic tumor evolution with high fidelity may contribute to better predictive tools for designing tumor therapy in the clinic. However, attempts to model tumor growth have mainly been developed and validated using data from xenograft mouse models, which fail to capture important aspects of tumorigenesis including tumor-initiating events and interactions with the immune system. In the present study, we investigate tumor growth and therapy dynamics in a mouse model of de novo carcinogenesis that closely recapitulates tumor initiation, progression and maintenance in vivo. We show that the rate of tumor growth and the effects of therapy are highly variable and mouse specific using a Gompertz model to describe tumor growth and a two-compartment pharmacokinetic/ pharmacodynamic model to describe the effects of therapy in mice treated with 5-FU. We show that inter-mouse growth variability is considerably larger than intra-mouse variability and that there is a correlation between tumor growth and drug kill rates. Our results show that in vivo tumor growth and regression in a double transgenic mouse model are highly variable both within and between subjects and that mathematical models can be used to capture the overall characteristics of this variability. In order for these models to become useful tools in the design of optimal therapy strategies and ultimately in clinical practice, a subject-specific modelling strategy is necessary, rather than approaches that are based on the average behavior of a given subject population which could provide erroneous results.

  20. Novel Transgenic Mouse Model for Studying Human Serum Albumin as a Biomarker of Carcinogenic Exposure.

    Science.gov (United States)

    Sheng, Jonathan; Wang, Yi; Turesky, Robert J; Kluetzman, Kerri; Zhang, Qing-Yu; Ding, Xinxin

    2016-05-16

    Albumin is a commonly used serum protein for studying human exposure to xenobiotic compounds, including therapeutics and environmental pollutants. Often, the reactivity of albumin with xenobiotic compounds is studied ex vivo with human albumin or plasma/serum samples. Some studies have characterized the reactivity of albumin with chemicals in rodent models; however, differences between the orthologous peptide sequences of human and rodent albumins can result in the formation of different types of chemical-protein adducts with different interaction sites or peptide sequences. Our goal is to generate a human albumin transgenic mouse model that can be used to establish human protein biomarkers of exposure to hazardous xenobiotics for human risk assessment via animal studies. We have developed a human albumin transgenic mouse model and characterized the genotype and phenotype of the transgenic mice. The presence of the human albumin gene in the genome of the model mouse was confirmed by genomic PCR analysis, whereas liver-specific expression of the transgenic human albumin mRNA was validated by RT-PCR analysis. Further immunoblot and mass spectrometry analyses indicated that the transgenic human albumin protein is a full-length, mature protein, which is less abundant than the endogenous mouse albumin that coexists in the serum of the transgenic mouse. The transgenic protein was able to form ex vivo adducts with a genotoxic metabolite of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a procarcinogenic heterocyclic aromatic amine formed in cooked meat. This novel human albumin transgenic mouse model will facilitate the development and validation of albumin-carcinogen adducts as biomarkers of xenobiotic exposure and/or toxicity in humans.

  1. A novel method of sampling gingival crevicular fluid from a mouse model of periodontitis.

    Science.gov (United States)

    Matsuda, Shinji; Movila, Alexandru; Suzuki, Maiko; Kajiya, Mikihito; Wisitrasameewong, Wichaya; Kayal, Rayyan; Hirshfeld, Josefine; Al-Dharrab, Ayman; Savitri, Irma J; Mira, Abdulghani; Kurihara, Hidemi; Taubman, Martin A; Kawai, Toshihisa

    2016-11-01

    Using a mouse model of silk ligature-induced periodontal disease (PD), we report a novel method of sampling mouse gingival crevicular fluid (GCF) to evaluate the time-dependent secretion patterns of bone resorption-related cytokines. GCF is a serum transudate containing host-derived biomarkers which can represent cellular response in the periodontium. As such, human clinical evaluations of PD status rely on sampling this critical secretion. At the same time, a method of sampling GCF from mice is absent, hindering the translational value of mouse models of PD. Therefore, we herein report a novel method of sampling GCF from a mouse model of periodontitis, involving a series of easy steps. First, the original ligature used for induction of PD was removed, and a fresh ligature for sampling GCF was placed in the gingival crevice for 10min. Immediately afterwards, the volume of GCF collected in the sampling ligature was measured using a high precision weighing balance. The sampling ligature containing GCF was then immersed in a solution of PBS-Tween 20 and subjected to ELISA. This enabled us to monitor the volume of GCF and detect time-dependent changes in the expression of such cytokines as IL-1b, TNF-α, IL-6, RANKL, and OPG associated with the levels of alveolar bone loss, as reflected in GCF collected from a mouse model of PD. Therefore, this novel GCF sampling method can be used to measure various cytokines in GCF relative to the dynamic changes in periodontal bone loss induced in a mouse model of PD. Copyright © 2016. Published by Elsevier B.V.

  2. Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines

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    C. Dirk Keene

    2016-06-01

    Full Text Available Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD, have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1 cerebrospinal fluid (CSF AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2 structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG, and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3 cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines

  3. Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines.

    Science.gov (United States)

    Keene, C Dirk; Darvas, Martin; Kraemer, Brian; Liggitt, Denny; Sigurdson, Christina; Ladiges, Warren

    2016-01-01

    Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1) cerebrospinal fluid (CSF) AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2) structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG), and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3) cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines and standards

  4. The pathological phenotypes of human TDP-43 transgenic mouse models are independent of downregulation of mouse Tdp-43.

    Directory of Open Access Journals (Sweden)

    Ya-Fei Xu

    Full Text Available Tar DNA binding protein 43 (TDP-43 is the major component of pathological deposits in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP and in amyotrophic lateral sclerosis (ALS. It has been reported that TDP-43 transgenic mouse models expressing human TDP-43 wild-type or ALS-associated mutations recapitulate certain ALS and FTLD pathological phenotypes. Of note, expression of human TDP-43 (hTDP-43 reduces the levels of mouse Tdp-43 (mTdp-43. However, it remained unclear whether the mechanisms through which TDP-43 induces ALS or FTLD-like pathologies resulted from a reduction in mTdp-43, an increase in hTDP-43, or a combination of both. In elucidating the role of mTdp-43 and hTDP-43 in hTDP-43 transgenic mice, we observed that reduction of mTdp-43 in non-transgenic mice by intraventricular brain injection of AAV1-shTardbp leads to a dramatic increase in the levels of splicing variants of mouse sortilin 1 and translin. However, the levels of these two abnormal splicing variants are not increased in hTDP-43 transgenic mice despite significant downregulation of mTdp-43 in these mice. Moreover, further downregulation of mTdp-43 in hTDP-43 hemizygous mice, which are asymptomatic, to the levels equivalent to that of mTdp-43 in hTDP-43 homozygous mice does not induce the pathological phenotypes observed in the homozygous mice. Lastly, the number of dendritic spines and the RNA levels of TDP-43 RNA targets critical for synapse formation and function are significantly decreased in symptomatic homozygous mice. Together, our findings indicate that mTdp-43 downregulation does not lead to a loss of function mechanism or account for the pathological phenotypes observed in hTDP-43 homozygous mice because hTDP-43 compensates for the reduction, and associated functions of mTdp-43. Rather, expression of hTDP-43 beyond a certain threshold leads to abnormal metabolism of TDP-43 RNA targets critical for neuronal structure and function, which might

  5. The pathological phenotypes of human TDP-43 transgenic mouse models are independent of downregulation of mouse Tdp-43.

    Science.gov (United States)

    Xu, Ya-Fei; Prudencio, Mercedes; Hubbard, Jaime M; Tong, Jimei; Whitelaw, Ena C; Jansen-West, Karen; Stetler, Caroline; Cao, Xiangkun; Song, John; Zhang, Yong-Jie

    2013-01-01

    Tar DNA binding protein 43 (TDP-43) is the major component of pathological deposits in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in amyotrophic lateral sclerosis (ALS). It has been reported that TDP-43 transgenic mouse models expressing human TDP-43 wild-type or ALS-associated mutations recapitulate certain ALS and FTLD pathological phenotypes. Of note, expression of human TDP-43 (hTDP-43) reduces the levels of mouse Tdp-43 (mTdp-43). However, it remained unclear whether the mechanisms through which TDP-43 induces ALS or FTLD-like pathologies resulted from a reduction in mTdp-43, an increase in hTDP-43, or a combination of both. In elucidating the role of mTdp-43 and hTDP-43 in hTDP-43 transgenic mice, we observed that reduction of mTdp-43 in non-transgenic mice by intraventricular brain injection of AAV1-shTardbp leads to a dramatic increase in the levels of splicing variants of mouse sortilin 1 and translin. However, the levels of these two abnormal splicing variants are not increased in hTDP-43 transgenic mice despite significant downregulation of mTdp-43 in these mice. Moreover, further downregulation of mTdp-43 in hTDP-43 hemizygous mice, which are asymptomatic, to the levels equivalent to that of mTdp-43 in hTDP-43 homozygous mice does not induce the pathological phenotypes observed in the homozygous mice. Lastly, the number of dendritic spines and the RNA levels of TDP-43 RNA targets critical for synapse formation and function are significantly decreased in symptomatic homozygous mice. Together, our findings indicate that mTdp-43 downregulation does not lead to a loss of function mechanism or account for the pathological phenotypes observed in hTDP-43 homozygous mice because hTDP-43 compensates for the reduction, and associated functions of mTdp-43. Rather, expression of hTDP-43 beyond a certain threshold leads to abnormal metabolism of TDP-43 RNA targets critical for neuronal structure and function, which might be responsible

  6. Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis.

    Science.gov (United States)

    Ye, Jing; Jiang, Rong; Cui, Min; Zhu, Bibo; Sun, Leqiang; Wang, Yueyun; Zohaib, Ali; Dong, Qian; Ruan, Xindi; Song, Yunfeng; He, Wen; Chen, Huanchun; Cao, Shengbo

    2014-09-15

    Japanese encephalitis virus (JEV) is a neurotropic flavivirus that causes Japanese encephalitis (JE), which leads to high fatality rates in human. Tumor necrosis factor alpha (TNF-α) is a key factor that mediates immunopathology in the central nervous system (CNS) during JE. Etanercept is a safe anti-TNF-α drug that has been commonly used in the treatment of various human autoimmune diseases. The effect of etanercept on JE was investigated with a JEV-infected mouse model. Four groups of mice were assigned to receive injections of phosphate-buffered saline, etanercept, JEV, or JEV plus etanercept. Inflammatory responses in mouse brains and mortality of mice were evaluated within 23 days post infection. The in vitro assay with mouse neuron/glia cultures showed that etanercept treatment reduced the inflammatory response induced by JEV infection. In vivo experiments further demonstrated that administration of etanercept protected mice from JEV-induced lethality. Neuronal damage, glial activation, and secretion of proinflammatory cytokines were found to be markedly decreased in JEV-infected mice that received etanercept treatment. Additionally, etanercept treatment restored the integrity of the blood-brain barrier and reduced viral load in mouse brains. Etanercept effectively reduces the inflammation and provides protection against acute encephalitis in a JEV-infected mouse model. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. B-cell anergy induces a Th17 shift in a novel B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse.

    Science.gov (United States)

    Carrascal, Jorge; Carrillo, Jorge; Arpa, Berta; Egia-Mendikute, Leire; Rosell-Mases, Estela; Pujol-Autonell, Irma; Planas, Raquel; Mora, Conchi; Mauricio, Dídac; Ampudia, Rosa Maria; Vives-Pi, Marta; Verdaguer, Joan

    2016-03-01

    Autoreactive B lymphocytes play a key role as APCs in diaebetogenesis. However, it remains unclear whether B-cell tolerance is compromised in NOD mice. Here, we describe a new B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse, where the transgenes derive from an islet-infiltrating B lymphocyte of a (8.3-NODxNOR) F1 mouse. The 116C-NOD mouse produces clonal B lymphocytes with pancreatic islet beta cell specificity. The incidence of T1D in 116C-NOD mice is decreased in both genders when compared with NOD mice. Moreover, several immune selection mechanisms (including clonal deletion and anergy) acting on the development, phenotype, and function of autoreactive B lymphocytes during T1D development have been identified in the 116C-NOD mouse. Surprisingly, a more accurate analysis revealed that, despite their anergic phenotype, 116C B cells express some costimulatory molecules after activation, and induce a T-cell shift toward a Th17 phenotype. Furthermore, this shift on T lymphocytes seems to occur not only when both T and B cells contact, but also when helper T (Th) lineage is established. The 116C-NOD mouse model could be useful to elucidate the mechanisms involved in the generation of Th-cell lineages. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. A physiologically-based kinetic model for the prediction of plasma cholesterol concentrations in the mouse.

    Science.gov (United States)

    van de Pas, Niek C A; Woutersen, Ruud A; van Ommen, Ben; Rietjens, Ivonne M C M; de Graaf, Albert A

    2011-05-01

    The LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) concentrations are determined by the activity of a complex network of reactions in several organs. Physiologically-based kinetic (PBK) computational models can be used to describe these different reactions in an integrated, quantitative manner. A PBK model to predict plasma cholesterol levels in the mouse was developed, validated, and analyzed. Kinetic parameters required for defining the model were obtained using data from published experiments. To construct the model, a set of appropriate submodels was selected from a set of 65,536 submodels differing in the kinetic expressions of the reactions. A submodel was considered appropriate if it had the ability to correctly predict an increased or decreased plasma cholesterol level for a training set of 5 knockout mouse strains. The model thus defined consisted of 8 appropriate submodels and was validated using data from an independent set of 9 knockout mouse strains. The model prediction is the average prediction of 8 appropriate submodels. Remarkably, these submodels had in common that the rate of cholesterol transport from the liver to HDL was not dependent on hepatic cholesterol concentrations. The model appeared able to accurately predict in a quantitative way the plasma cholesterol concentrations of all 14 knockout strains considered, including the frequently used Ldlr-/- and Apoe-/- mouse strains. The model presented is a useful tool to predict the effect of knocking out genes that act in important steps in cholesterol metabolism on total plasma cholesterol, HDL-C and LDL-C in the mouse. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Evaluation of synthetic vascular grafts in a mouse carotid grafting model.

    Directory of Open Access Journals (Sweden)

    Alex H P Chan

    Full Text Available Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endothelialisation of the PCL grafts, assessed by scanning electron microscopy (SEM analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP. This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days. We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance.

  10. High-Throughput Automated Phenotyping of Two Genetic Mouse Models of Huntington's Disease.

    Science.gov (United States)

    Balci, Fuat; Oakeshott, Stephen; Shamy, Jul Lea; El-Khodor, Bassem F; Filippov, Igor; Mushlin, Richard; Port, Russell; Connor, David; Paintdakhi, Ahmad; Menalled, Liliana; Ramboz, Sylvie; Howland, David; Kwak, Seung; Brunner, Dani

    2013-07-11

    Phenotyping with traditional behavioral assays constitutes a major bottleneck in the primary screening, characterization, and validation of genetic mouse models of disease, leading to downstream delays in drug discovery efforts. We present a novel and comprehensive one-stop approach to phenotyping, the PhenoCube™. This system simultaneously captures the cognitive performance, motor activity, and circadian patterns of group-housed mice by use of home-cage operant conditioning modules (IntelliCage) and custom-built computer vision software. We evaluated two different mouse models of Huntington's Disease (HD), the R6/2 and the BACHD in the PhenoCube™ system. Our results demonstrated that this system can efficiently capture and track alterations in both cognitive performance and locomotor activity patterns associated with these disease models. This work extends our prior demonstration that PhenoCube™ can characterize circadian dysfunction in BACHD mice and shows that this system, with the experimental protocols used, is a sensitive and efficient tool for a first pass high-throughput screening of mouse disease models in general and mouse models of neurodegeneration in particular.

  11. A new transgenic mouse model for conditional overexpression of the Polycomb Group protein EZH2.

    Science.gov (United States)

    Koppens, Martijn A J; Tanger, Ellen; Nacerddine, Karim; Westerman, Bart; Song, Ji-Ying; van Lohuizen, Maarten

    2017-04-01

    The Polycomb Group protein EZH2 is upregulated in most prostate cancers, and its overexpression is associated with poor prognosis. Most insights into the functional role of EZH2 in prostate cancer have been gained using cell lines and EZH2 inactivation studies. However, the question remains whether overexpression of EZH2 can initiate prostate tumourigenesis or drive tumour progression. Appropriate transgenic mouse models that are required to answer such questions are lacking. We developed one such transgenic mouse model for conditional overexpression of Ezh2. In this transgene, Ezh2 and Luciferase are transcribed from a single open reading frame. The latter gene enables intravital bioluminescent imaging of tissues expressing this transgene, allowing the detection of tumour outgrowth and potential metastatic progression over time. Prostate-specific Ezh2 overexpression by crossbreeding with Probasin-Cre mice led to neoplastic prostate lesions at low incidence and with a long latency. Compounding a previously described Bmi1-transgene and Pten-deficiency prostate cancer mouse model with the Ezh2 transgene did not enhance tumour progression or drive metastasis formation. In conclusion, we here report the generation of a wildtype Ezh2 overexpression mouse model that allows for intravital surveillance of tissues with activated transgene. This model will be an invaluable tool for further unravelling the role of EZH2 in cancer.

  12. Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models.

    Directory of Open Access Journals (Sweden)

    Quan Rao

    Full Text Available Mouse models are commonly used for studying hepatocellular carcinoma (HCC biology and exploring new therapeutic interventions. Currently three main modalities of HCC mouse models have been extensively employed in pre-clinical studies including chemically induced, transgenic and transplantation models. Among them, transplantation models are preferred for evaluating in vivo drug efficacy in pre-clinical settings given the short latency, uniformity in size and close resemblance to tumors in patients. However methods used for establishing orthotopic HCC transplantation mouse models are diverse and fragmentized without a comprehensive comparison. Here, we systemically evaluate four different approaches commonly used to establish HCC mice in preclinical studies, including intravenous, intrasplenic, intrahepatic inoculation of tumor cells and intrahepatic tissue implantation. Four parameters--the latency period, take rates, pathological features and metastatic rates--were evaluated side-by-side. 100% take rates were achieved in liver with intrahepatic, intrasplenic inoculation of tumor cells and intrahepatic tissue implantation. In contrast, no tumor in liver was observed with intravenous injection of tumor cells. Intrahepatic tissue implantation resulted in the shortest latency with 0.5 cm (longitudinal diameter tumors found in liver two weeks after implantation, compared to 0.1cm for intrahepatic inoculation of tumor cells. Approximately 0.1cm tumors were only visible at 4 weeks after intrasplenic inoculation. Uniform, focal and solitary tumors were formed with intrahepatic tissue implantation whereas multinodular, dispersed and non-uniform tumors produced with intrahepatic and intrasplenic inoculation of tumor cells. Notably, metastasis became visible in liver, peritoneum and mesenterium at 3 weeks post-implantation, and lung metastasis was visible after 7 weeks. T cell infiltration was evident in tumors, resembling the situation in HCC patients

  13. Transgenic mouse models to study Gpr54/kisspeptin physiology.

    Science.gov (United States)

    Colledge, W H

    2009-01-01

    Four transgenic mouse lines have been generated with mutations in the Gpr54 gene and two lines with mutations in the Kiss1 gene. In general, the phenotypes of all these mutant mice are very similar and provide evidence that these molecules constitute an authentic receptor/ligand pair with no obvious redundancy or overlap with other signaling pathways. The mutant mice all fail to undergo pubertal maturation and show poor development of the gonads and infertility with low sex steroid and gonadotrophic hormone levels (hypogonadotrophic hypogonadism). Spermatogenesis and ovulation are severely impaired and mutant females do not show estrous cycling. The gonads and the anterior pituitary retain functional responses to hormonal stimulation however, consistent with the primary defect being a failure to secrete gonadotrophin releasing hormone (GnRH) from the hypothalamus. Slight differences between the phenotype of some of the mutant lines may reflect the type of mutation carried by each line. These mutant mice are being used to interrogate the function of Gpr54 and Kiss1 in key aspects of mammalian reproduction in vivo including the role of these proteins in the generation of the pre-ovulatory luteinizing hormone (LH) surge and aspects of sexual behavior. They provide a useful resource to further understand the hypothalamic regulation of mammalian reproduction, its integration with the pituitary-gonadal axis and to study the potential function of Gpr54 and Kiss1 in peripheral tissues.

  14. T2 weighted MRI for assessing renal lesions in transgenic mouse models of tuberous sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Kalogerou, Maria; Zhang, Yadan; Yang, Jian; Garrahan, Nigel [Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN (United Kingdom); Paisey, Stephen; Tokarczuk, Paweł; Stewart, Andrew [School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX (United Kingdom); Gallacher, John [Department of Primary Care and Public Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4YS (United Kingdom); Sampson, Julian R. [Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN (United Kingdom); Shen, Ming Hong, E-mail: shenmh@cf.ac.uk [Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN (United Kingdom)

    2012-09-15

    Objective: Transgenic mouse models of tuberous sclerosis (TSC) develop renal cysts, cystadenomas, solid adenomas and carcinomas. Identification and characterisation of these lesions in vivo may help in TSC pre-clinical trials. This study was to evaluate T2 weighted MRI for assessment of renal lesions in two Tsc mouse models. Materials and Methods: Tsc1{sup +/−}, Tsc2{sup +/−} and wild type mice were subjected to a first MRI scan at 12 months of age and a second scan 2 months later. One Tsc2{sup +/−} mouse was treated with rapamycin for two months after the initial scan. Immediately following the second scan, mice were sacrificed and MRI images were compared to renal histological findings. Results: MRI identified all types of Tsc-associated renal lesions in both Tsc1{sup +/−} and Tsc2{sup +/−} mice. The smallest detectable lesions were <0.1 mm{sup 3}. Eighty three percent of all renal lesions detected in the first scan were re-identified in the second scan. By MRI, these lesions demonstrated significant growth in the 9 untreated Tsc1{sup +/−} and Tsc2{sup +/−} mice but shrinkage in the rapamycin treated Tsc2{sup +/−} mouse. Between the two scans, MRI also revealed significant increase in both the total number and volume of lesions in untreated mice and decrease in the rapamycin treated mouse, respectively. In comparison to histological analysis MRI detected most cysts and cystadenomas (66%) but only a minority of solid tumours (29%). Conclusion: These results suggest that T2 weighted MRI may be a useful tool for assessing some renal lesions in pre-clinical studies using Tsc mouse models. However, improved sensitivity for T2 weighted MRI is required, particularly for solid renal lesions.

  15. Modeling motivational deficits in mouse models of schizophrenia: behavior analysis as a guide for neuroscience.

    Science.gov (United States)

    Ward, Ryan D; Simpson, Eleanor H; Kandel, Eric R; Balsam, Peter D

    2011-05-01

    In recent years it has become possible to develop animal models of psychiatric disease in genetically modified mice. While great strides have been made in the development of genetic and neurobiological tools with which to model psychiatric disease, elucidation of neural and molecular mechanisms thought to underlie behavioral phenotypes has been hindered by an inadequate analysis of behavior. This is unfortunate given the fact that the experimental analysis of behavior has created powerful methods for isolating and describing the functional properties of behavioral mechanisms that are capable of providing deep understanding of behavioral phenotypes. A better understanding of the biological basis of normal behavior and its disturbance in psychiatric disease will require the application of these rigorous behavior analytic tools to animal models. In this review we provide an example of a merging of genetic and behavioral methods and illustrate its utility in the analysis of a mouse model of the motivational deficits in schizophrenia. The synergy between basic behavior analysis, neuroscience, and animal models of psychiatric disease has great potential for achieving a deeper understanding of behavior and its neurobiological mechanisms as well as for leading to improvements in diagnosis and treatment in clinical settings. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. GFAP expression as an indicator of disease severity in mouse models of Alexander disease.

    Science.gov (United States)

    Jany, Paige L; Hagemann, Tracy L; Messing, Albee

    2013-01-01

    AxD (Alexander disease) is a rare disorder caused by heterozygous mutations in GFAP (glial fibrillary acidic protein) resulting in accumulation of the GFAP protein and elevation of Gfap mRNA. To test whether GFAP itself can serve as a biomarker of disease status or progression, we investigated two independent measures of GFAP expression in AxD mouse models, one using a genetic reporter of promoter activity and the other quantifying GFAP protein directly in a manner that could also be employed in human studies. Using a transgenic reporter line that expresses firefly luciferase under the control of the murine Gfap promoter (Gfap-luc), we found that luciferase activity reflected the regional CNS (central nervous system) variability of Gfap mRNA in Gfap(+/+) mice, and increased in mice containing a point mutation in Gfap that mimics a common human mutation in AxD (R239H in the human sequence, and R236H in the murine sequence). In a second set of studies, we quantified GFAP protein in CSF (cerebrospinal fluid) taken from three different AxD mouse models and littermate controls. GFAP levels in CSF were increased in all three AxD models, in a manner corresponding to the concentrations of GFAP in brain. These studies demonstrate that transactivation of the Gfap promoter is an early and sustained indicator of the disease process in the mouse. Furthermore, GFAP in CSF serves as a potential biomarker that is comparable between mouse models and human patients.

  17. Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model

    NARCIS (Netherlands)

    H. Jiang (Hao); K. Clise-Dwyer (Karen); K.E. Ruisaard (Kathryn); X. Fan (Xuejun); W. Tian (Weihua); J. Gumin (Joy); M.L.M. Lamfers (Martine); A. Kleijn (Anne); F.F. Lang (Frederick); S. Yung (Sun); L.M. Vence (Luis); C. Gomez-Manzano (Candelaria); J. Fueyo (Juan)

    2014-01-01

    textabstractBackground: Emerging evidence suggests anti-cancer immunity is involved in the therapeutic effect induced by oncolytic viruses. Here we investigate the effect of Delta-24-RGD oncolytic adenovirus on innate and adaptive anti-glioma immunity. Design: Mouse GL261-glioma model was set up in

  18. Breeding a PKU-mouse model on Phe-free diet, is it possible?

    DEFF Research Database (Denmark)

    Dagnæs-Hansen, Frederik; Johansen, Karen Singers; Vorup-Jensen, Thomas

    2014-01-01

    is therefore widely used model in PKU research. The Pahenu2 mutation has been transferred to the inbred C57BL/6 mouse strain. Breeding colonies on both inbred strains have been established at Aarhus University. Recently an attempt to breed homozygous animals on a Phe-free diet was attempted in order to reduce...

  19. Comparative mRNA analysis of behavioral and genetic mouse models of aggression

    NARCIS (Netherlands)

    Malki, Karim; Tosto, Maria G.; Pain, Oliver; Sluyter, Frans; Mineur, Yann S.; Crusio, Wim E.; de Boer, Sietse; Sandnabba, Kenneth N.; Kesserwani, Jad; Robinson, Edward; Schalkwyk, Leonard C.; Asherson, Philip

    Mouse models of aggression have traditionally compared strains, most notably BALB/cJ and C57BL/6. However, these strains were not designed to study aggression despite differences in aggression-related traits and distinct reactivity to stress. This study evaluated expression of genes differentially

  20. A novel brain trauma model in the mouse : effects of dexamethasone treatment

    NARCIS (Netherlands)

    Hortobágyi, Tibor; Hortobagyi, S; Gorlach, C; Harkany, T; Benbyo, Z; Gorogh, T; Nagel, W; Wahl, M

    2000-01-01

    We describe a novel methodological approach for inducing cold lesion in the mouse as a model of human cortical contusion trauma. To validate its reproducibility and reliability, dexamethasone (Dxm) was repeatedly applied to demonstrate possible antioedematous drug effects. Following tho induction of

  1. Role of lipotoxicity in insulin resistance in subtotally nephrectomized mouse model

    Directory of Open Access Journals (Sweden)

    Laetitia Koppe

    2012-06-01

    In subtotally nephrectomized mouse model we showed an ectopic intramuscular and intrahepatic lipid redistribution concomitant with insulin resistance. Insulin resistance and lipotoxicity may represent the missing links (beyond the classical cardiovascular risk factors that may help explain the increased risk of cardiovascular disease in CKD.

  2. Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Athanassios Fragoulis

    2017-08-01

    Conclusion: In summary, these findings show that methysticin administration activates the Nrf2 pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD. Therefore, kavalactones might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.

  3. Activity-Dependent Changes in MAPK Activation in the Angelman Syndrome Mouse Model

    Science.gov (United States)

    Filonova, Irina; Trotter, Justin H.; Banko, Jessica L.; Weeber, Edwin J.

    2014-01-01

    Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal "UBE3A" gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular…

  4. A modified immune tolerant mouse model to study the immunogenicity of recombinant human interferon beta

    NARCIS (Netherlands)

    Abdolvahab, Mohadeseh Haji; Brinks, Vera; Schellekens, Huub

    2014-01-01

    Interferon beta may induce antibodies in multiple sclerosis patients and the incidence of immunogenicity depends on the type of product. These antibodies can reduce the efficacy of interferon beta. Two transgenic immune tolerant mouse models for human interferon beta (hIFNβ) (C57Bl/6, and

  5. Transgenic mouse models to study the role of APOE in hyperlipidemia and atherosclerosis

    NARCIS (Netherlands)

    Hofker, M.H.; Vlijmen, B.J.M. van; Havekes, L.M.

    1998-01-01

    Transgenic technologies have provided a series of very useful mouse models to study hyperlipidemia and atherosclerosis. Normally, mice carry cholesterol mainly in the high density lipoprotein (HDL) sized lipoproteins, and have low density lipoprotein (LDL) and very low density lipoprotein (VLDL)

  6. Multiple faces of FoxM1 transcription factor: Lessons from transgenic mouse models

    National Research Council Canada - National Science Library

    Kalin, Tanya V; Ustiyan, Vladimir; Kalinichenko, Vladimir V

    2011-01-01

    .... In this review, we discussed the role of FoxM1 in different cell lineages using recent data from transgenic mouse models with conditional "gain-of-function" and "loss-of-function" of FoxM1, as well...

  7. NOD mouse model for Sjögren's syndrome: lack of longitudinal stability

    NARCIS (Netherlands)

    Lodde, B. M.; Mineshiba, F.; Kok, M. R.; Wang, J.; Zheng, C.; Schmidt, M.; Cotrim, A. P.; Kriete, M.; Tak, P. P.; Baum, B. J.

    2006-01-01

    OBJECTIVES: The non-obese diabetic (NOD) mouse is not only a widely used model for diabetes mellitus type I, but also for the chronic autoimmune disease Sjögren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno-associated

  8. Reduced activity-dependent protein levels in a mouse model of the fragile X premutation

    NARCIS (Netherlands)

    R.E. von Leden (Ramona); L.C. Curley (Lindsey); G.D. Greenberg (Gian); M.R. Hunsaker (Michael); R. Willemsen (Rob); R.F. Berman (Robert)

    2014-01-01

    textabstractEnvironmental enrichment results in increased levels of Fmrp in brain and increased dendritic complexity. The present experiment evaluated activity-dependent increases in Fmrp levels in the motor cortex in response to training on a skilled forelimb reaching task in the CGG KI mouse model

  9. Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

    Science.gov (United States)

    The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...

  10. Evaluation of the sensitizing potential of food proteins using two mouse models

    NARCIS (Netherlands)

    Smit, J.; Zeeuw-Brouwer, M.L.D.; Roest, M. van; Jong, G. de; Bilsen, J. van

    2016-01-01

    The current methodology to identify allergenic food proteins is effective in identifying those that are likely to cross-react with known allergens. However, most assays show false positive results for low/non-allergens. Therefore, an ex vivo/in vitro DC-T cell assay and an in vivo mouse model were

  11. Allergen immunotherapy induces a suppressive memory response mediated by IL-10 in a mouse asthma model

    NARCIS (Netherlands)

    Vissers, Joost L. M.; van Esch, Betty C. A. M.; Hofman, Gerard A.; Kapsenberg, Martien L.; Weller, Frank R.; van Oosterhout, Antoon J. M.

    2004-01-01

    Background: Human studies have demonstrated that allergen immunotherapy induces memory suppressive responses and IL-10 production by allergen-specific T cells. Previously, we established a mouse model in which allergen immunotherapy was effective in the suppression of allergen-induced asthma

  12. Novel approaches to identify low-penetrance cancer susceptibility genes using mouse models.

    Science.gov (United States)

    de Koning, John P; Mao, Jian-Hua; Balmain, Allan

    2003-01-01

    Studies of cancer predisposition have largely concentrated on the role of high-penetrance susceptibility genes. Less than 10% of the total human tumor burden, however, is accounted for by mutations in these genes. More genetic variation in cancer risk is likely to be due to commoner but lower penetrance alleles. In man, such modifier genes will be difficult to find since they do not segregate as single Mendelian traits. The mouse offers a powerful system for studying polygenic traits such as cancer and has been widely used for this purpose. Novel approaches that might accelerate the identification of these low-penetrance cancer susceptibility genes by using mouse models will be discussed.

  13. Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model

    OpenAIRE

    Laura ePsotta; Carolin eRockahr; Michael eGruss; Elmar eKirches; Katharina A Braun; Katharina A Braun; Volkmar eLessmann; Volkmar eLessmann; Joerg eBock; Thomas eEndres

    2015-01-01

    There is increasing evidence that brain-derived neurotrophic factor (BDNF) plays a crucial role in AD pathology. A number of studies demonstrated that AD patients exhibit reduced BDNF levels in the brain and the blood serum, and in addition, several animal-based studies indicated a potential protective effect of BDNF against Aβ-induced neurotoxicity. In order to further investigate the role of BDNF in the etiology of AD, we created a novel mouse model by crossing a well-established AD mouse m...

  14. The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men.

    Energy Technology Data Exchange (ETDEWEB)

    Lehman, J M [University of Alabama, Birmingham; Michaud III, Edward J [ORNL; Schoeb, T [University of Alabama, Birmingham; Aydin Son, Yesim [University of Tennessee, Knoxville (UTK); Miller, M [University of Alabama, Birmingham; Yoder, Bradley [University of Alabama, Birmingham

    2008-08-01

    The Oak Ridge Polycystic Kidney (ORPK) mouse was described nearly 14 years ago as a model for human recessive polycystic kidney disease. The ORPK mouse arose through integration of a transgene into an intron of the Ift88 gene resulting in a hypomorphic allele (Ift88Tg737Rpw). The Ift88Tg737Rpw mutation impairs intraflagellar transport (IFT), a process required for assembly of motile and immotile cilia. Historically, the primary immotile cilium was thought to have minimal importance for human health; however, a rapidly expanding number of human disorders have now been attributed to ciliary defects. Importantly, many of these phenotypes are present and can be analyzed using the ORPK mouse. In this review, we highlight the research conducted using the OPRK mouse and the phenotypes shared with human cilia disorders. Furthermore, we describe an additional follicular dysplasia phenotype in the ORPK mouse, which alongside the ectodermal dysplasias seen in human Ellis-van Creveld and Sensenbrenner's syndromes, suggests an unappreciated role for primary cilia in the skin and hair follicle.

  15. Behavioral Phenotyping Assays for Genetic Mouse Models of Neurodevelopmental, Neurodegenerative, and Psychiatric Disorders.

    Science.gov (United States)

    Sukoff Rizzo, Stacey J; Crawley, Jacqueline N

    2017-02-08

    Animal models offer heuristic research tools to understand the causes of human diseases and to identify potential treatments. With rapidly evolving genetic engineering technologies, mutations identified in a human disorder can be generated in the mouse genome. Phenotypic outcomes of the mutation are then explicated to confirm hypotheses about causes and to discover effective therapeutics. Most neurodevelopmental, neurodegenerative, and psychiatric disorders are diagnosed primarily by their prominent behavioral symptoms. Mouse behavioral assays analogous to the human symptoms have been developed to analyze the consequences of mutations and to evaluate proposed therapeutics preclinically. Here we describe the range of mouse behavioral tests available in the established behavioral neuroscience literature, along with examples of their translational applications. Concepts presented have been successfully used in other species, including flies, worms, fish, rats, pigs, and nonhuman primates. Identical strategies can be employed to test hypotheses about environmental causes and gene × environment interactions.

  16. The Event Coordination Notation: Behaviour Modelling Beyond Mickey Mouse

    DEFF Research Database (Denmark)

    Jepsen, Jesper; Kindler, Ekkart

    2015-01-01

    generating fully functional software from a combination of class diagrams and ECNO models. What is more, software generated from ECNO models, integrates with existing software and software generated by other technologies. ECNO started out from some challenges in behaviour modelling and some requirements...

  17. Construction of a mouse model of factor VIII deficiency by gene targeting

    Energy Technology Data Exchange (ETDEWEB)

    Bi, L.; Lawler, A.; Gearhart, J. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)] [and others

    1994-09-01

    To develop a small animal model of hemophilia A for gene therapy experiments, we set out to construct a mouse model for factor VIII deficiency by gene targeting. First, we screened a mouse liver cDNA library using a human FVIII cDNA probe. We cloned a 2.6 Kb partial mouse factor VIII cDNA which extends from 800 base pairs of the 3{prime} end of exon 14 to the 5{prime} end of exon 26. A mouse genomic library made from strain 129 was then screened to obtain genomic fragments covering the exons desired for homologous recombination. Two genomic clones were obtained, and one covering exon 15 through 22 was used for gene targeting. To make gene targeting constructs, a 5.8 Kb genomic DNA fragment covering exons 15 to 19 of the mouse FVIII gene was subcloned, and the neo expression cassette was inserted into exons 16 and 17 separately by different strategies. These two constructs were named MFVIIIC-16 and MFVIIIC-17. The constructs were linearized and transfected into strain 129 mouse ES cells by electroporation. Factor VIII gene-knockout ES cell lines were selected by G-418 and screened by genomic Southern blots. Eight exon 16 targeted cell lines and five exon 17 targeted cell lines were obtained. Three cell lines from each construct were injected into blastocysts and surgically transferred into foster mothers. Multiple chimeric mice with 70-90% hair color derived from the ES-cell genotype were seen with both constructs. Germ line transmission of the ES-cell genotype has been obtained for the MFVIIIC-16 construct, and multiple hemophilia A carrier females have been identified. Factor VIII-deficient males will be conceived soon.

  18. Manipulation of DNA Repair Proficiency in Mouse Models of Colorectal Cancer

    Science.gov (United States)

    Boivin, Gregory P.

    2016-01-01

    Technical and biological innovations have enabled the development of more sophisticated and focused murine models that increasingly recapitulate the complex pathologies of human diseases, in particular cancer. Mouse models provide excellent in vivo systems for deciphering the intricacies of cancer biology within the context of precise experimental settings. They present biologically relevant, adaptable platforms that are amenable to continual improvement and refinement. We discuss how recent advances in our understanding of tumorigenesis and the underlying deficiencies of DNA repair mechanisms that drive it have been informed by using genetically engineered mice to create defined, well-characterized models of human colorectal cancer. In particular, we focus on how mechanisms of DNA repair can be manipulated precisely to create in vivo models whereby the underlying processes of tumorigenesis are accelerated or attenuated, dependent on the composite alleles carried by the mouse model. Such models have evolved to the stage where they now reflect the initiation and progression of sporadic cancers. The review is focused on mouse models of colorectal cancer and how insights from these models have been instrumental in shaping our understanding of the processes and potential therapies for this disease. PMID:27413734

  19. Establishment of a transgenic mouse model of corneal dystrophy overexpressing human BIGH3.

    Science.gov (United States)

    Liao, Xin; Cui, Hongping; Wang, Fang

    2013-11-01

    This study aimed to establish a transgenic mouse model of corneal dystrophy (CD) overexpressing the human transforming growth factor, β-induced, 68 kDa (TGFBI, also known as BIGH3) gene. A purified and linearized recombinant plasmid carrying the expression cassette BIGH3‑IRES‑EGFP was microinjected into the pronuclei of C57BL/6J mouse fertilized eggs under the control of the phosphoglycerate kinase (PGK) promoter. The expression of human BIGH3 in the transgenic mice was confirmed by PCR using DNA extracted from tail tissue. Four founder transgenic mice were identified by PCR and the increased expression of BIGH3 was observed in the corneas of the transgenic mice by RT-PCR and western blot analysis. The abnormal corneas with central opacity were observed in the transgenic mice by corneal photography. We concluded that the exogenous gene, BIGH3, was integrated successfully into the mouse genome through microinjection. In addition, the phenotype observed in this BIGH3 transgenic mouse model was similar to CD. Therefore, this transgenic model may prove useful in the investigation of the pathogenesis of CD.

  20. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation

    Science.gov (United States)

    Bartlett, Nathan W; Walton, Ross P; Edwards, Michael R; Aniscenko, Juliya; Caramori, Gaetano; Zhu, Jie; Glanville, Nicholas; Choy, Katherine J; Jourdan, Patrick; Burnet, Jerome; Tuthill, Tobias J; Pedrick, Michael S; Hurle, Michael J; Plumpton, Chris; Sharp, Nigel A; Bussell, James N; Swallow, Dallas M; Schwarze, Jurgen; Guy, Bruno; Almond, Jeffrey W; Jeffery, Peter K; Lloyd, Clare M; Papi, Alberto; Killington, Richard A; Rowlands, David J; Blair, Edward D; Clarke, Neil J; Johnston, Sebastian L

    2012-01-01

    Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations. PMID:18246079

  1. Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model.

    Science.gov (United States)

    Psotta, Laura; Rockahr, Carolin; Gruss, Michael; Kirches, Elmar; Braun, Katharina; Lessmann, Volkmar; Bock, Jörg; Endres, Thomas

    2015-01-01

    There is increasing evidence that brain-derived neurotrophic factor (BDNF) plays a crucial role in Alzheimer's disease (AD) pathology. A number of studies demonstrated that AD patients exhibit reduced BDNF levels in the brain and the blood serum, and in addition, several animal-based studies indicated a potential protective effect of BDNF against Aβ-induced neurotoxicity. In order to further investigate the role of BDNF in the etiology of AD, we created a novel mouse model by crossing a well-established AD mouse model (APP/PS1) with a mouse exhibiting a chronic BDNF deficiency (BDNF(+/-)). This new triple transgenic mouse model enabled us to further analyze the role of BDNF in AD in vivo. We reasoned that in case BDNF has a protective effect against AD pathology, an AD-like phenotype in our new mouse model should occur earlier and/or in more severity than in the APP/PS1-mice. Indeed, the behavioral analysis revealed that the APP/PS1-BDNF(+/-)-mice show an earlier onset of learning impairments in a two-way active avoidance task in comparison to APP/PS1- and BDNF(+/-)-mice. However in the Morris water maze (MWM) test, we could not observe an overall aggrevated impairment in spatial learning and also short-term memory in an object recognition task remained intact in all tested mouse lines. In addition to the behavioral experiments, we analyzed the amyloid plaque pathology in the APP/PS1 and APP/PS1-BDNF(+/-)-mice and observed a comparable plaque density in the two genotypes. Moreover, our results revealed a higher plaque density in prefrontal cortical compared to hippocampal brain regions. Our data reveal that higher cognitive tasks requiring the recruitment of cortical networks appear to be more severely affected in our new mouse model than learning tasks requiring mainly sub-cortical networks. Furthermore, our observations of an accelerated impairment in active avoidance learning in APP/PS1-BDNF(+/-)-mice further supports the hypothesis that BDNF deficiency

  2. Hydrodynamic Transfection for Generation of Novel Mouse Models for Liver Cancer Research

    Science.gov (United States)

    Chen, Xin; Calvisi, Diego F.

    2015-01-01

    Primary liver cancers, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, are leading causes of cancer-related death worldwide. Recent large-scale genomic approaches have identified a wide number of genes whose deregulation is associated with hepatocellular carcinoma and intrahepatic cholangiocarcinoma development. Murine models are critical tools to determine the oncogenic potential of these genes. Conventionally, transgenic or knockout mouse models are used for this purpose. However, several limitations apply to the latter models. Herein, we review a novel approach for stable gene expression in mouse hepatocytes by hydrodynamic injection in combination with Sleeping Beauty–mediated somatic integration. This method represents a flexible, reliable, and cost-effective tool to generate preclinical murine models for liver cancer research. Furthermore, it can be used as an in vivo transfection method to study biochemical cross talks among multiple pathways along hepatocarcinogenesis and to test the therapeutic potential of drugs against liver cancer. PMID:24480331

  3. Histopathological Evaluation of Skeletal Muscle with Specific Reference to Mouse Models of Muscular Dystrophy.

    Science.gov (United States)

    Terry, Rebecca L; Wells, Dominic J

    2016-12-01

    The muscular dystrophies are a diverse group of degenerative diseases for which many mouse models are available. These models are frequently used to assess potential therapeutic interventions and histological evaluation of multiple muscles is an important part of this assessment. Histological evaluation is especially useful when combined with tests of muscle function. This unit describes a protocol for necropsy, processing, cryosectioning, and histopathological evaluation of murine skeletal muscles, which is applicable to both models of muscular dystrophy and other neuromuscular conditions. Key histopathological features of dystrophic muscle are discussed using the mdx mouse (a model of Duchenne muscular dystrophy) as an example. Optimal handling during dissection, processing and sectioning is vital to avoid artifacts that can confound or prevent future analyses. Muscles carefully processed using this protocol are suitable for further evaluation using immunohistochemistry, immunofluorescence, special histochemical stains, and immuoblotting. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

  4. Immune Response to Human Metapneumovirus Infection: What We Have Learned from the Mouse Model

    Directory of Open Access Journals (Sweden)

    Nagarjuna R. Cheemarla

    2015-09-01

    Full Text Available Human Metapneumovirus (hMPV is a leading respiratory viral pathogen associated with bronchiolitis, pneumonia, and asthma exacerbation in young children, the elderly and immunocompromised individuals. The development of a potential vaccine against hMPV requires detailed understanding of the host immune system, which plays a significant role in hMPV pathogenesis, susceptibility and vaccine efficacy. As a result, animal models have been developed to better understand the mechanisms by which hMPV causes disease. Several animal models have been evaluated and established so far to study the host immune responses and pathophysiology of hMPV infection. However, inbred laboratory mouse strains have been one of the most used animal species for experimental modeling and therefore used for the studies of immunity and immunopathogenesis to hMPV. This review summarizes the contributions of the mouse model to our understanding of the immune response against hMPV infection.

  5. Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model

    Science.gov (United States)

    Roh, Kangsan; Cho, Sungrae; Park, Jae-hyun; Yoo, Byong Chul; Kim, Won-Ki; Kim, Seok-ki; Park, Kyewon; Kang, Hee; Ku, Jin-mo; Yeom, Chang-Hwan; Lee, Kyunghoon

    2017-01-01

    Acquired lymphedema is one of the most dreaded side effects of cancer treatment, such as surgical treatment or irradiation. However, due to the lack of appropriate animal models, there is no effective therapeutic method to cure acquired lymphedema. To develop a reproducible acquired lymphedema animal model, we devised a mouse hind limb model by removing a superficial inguinal lymph node, a popliteal lymph node, a deep inguinal lymph node, and the femoral lymphatic vessel. We measured the volume of lymphedematous leg and observed the change in level of hyaluronic acid (HA) and lymphangiogenic factors after injecting hyaluronidase. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the lymphedematous regions of our model, we confirmed that HA, a major component of extracellular matrix, accumulated to higher levels than in a normal mouse. This lymphedema volume was rapidly reduced by treating hyaluronidase. Following hyaluronidase injection, the lymphedematous region of our model resembled a normal hind limb. Our findings indicated that hyaluronidase promoted lymphangiogenesis on the lymphedematous limb. Based on hyaluronidase treatment in the lymphedematous region, this could potentially be a new therapeutic approach for acquired lymphedema mediated through the modification of the size of HA fragments. Impact statement In this manuscript, the essence of the work described in this manuscript involves the development of (1) a mouse limb model showing acquired lymphedema and (2) a potent therapeutic treatment using hyaluronidase to remedy acquired lymphedema in our model. In order to develop a reproducible acquired lymphedema animal model that reflects the most common symptoms experienced by lymphedema patients, we devised a mouse hind limb model by removing lymph nodes and lymphatics. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the

  6. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy

    OpenAIRE

    Kariya, Shingo; Park, Gyu-Hwan; Maeno-Hikichi, Yuka; Leykekhman, Olga; Lutz, Cathleen; Arkovitz, Marc S.; Landmesser, Lynn T.; Monani, Umrao R.

    2008-01-01

    Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the survival of motor neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of reduced SMN protein. In this study, we have used severe- and mild-SMN2 expressing mouse models of SMA as well as material from human patients to understand the initial stages of ...

  7. Mobile Laser Indirect Ophthalmoscope: For the Induction of Choroidal Neovascularization in a Mouse Model.

    Science.gov (United States)

    Weinberger, Dov; Bor-Shavit, Elite; Barliya, Tilda; Dahbash, Mor; Kinrot, Opher; Gaton, Dan D; Nisgav, Yael; Livnat, Tami

    2017-11-01

    This study aims to evaluate and standardize the reliability of a mobile laser indirect ophthalmoscope in the induction of choroidal neovascularization (CNV) in a mouse model. A diode laser indirect ophthalmoscope was used to induce CNV in pigmented male C57BL/6J mice. Standardization of spot size and laser intensity was determined using different aspheric lenses with increasing laser intensities applied around the optic disc. Development of CNV was evaluated 1, 5, and 14 days post laser application using fluorescein angiography (FA), histology, and choroidal flat mounts stained for the endothelial marker CD31 and FITC-dextran. Correlation between the number of laser hits to the number and size of developed CNV lesions was determined using flat mount choroid staining. The ability of intravitreally injected anti-human and anti-mouse VEGF antibodies to inhibit CNV induced by the mobile laser was evaluated. Laser parameters were standardized on 350 mW for 100 msec, using the 90 diopter lens to accomplish the highest incidence of Bruch's membrane rupture. CNV lesions' formation was validated on days 5 and 14 post laser injury, though FA showed leakage on as early as day 1. The number of laser hits was significantly correlated with the CNV area. CNV growth was successfully inhibited by both anti-human and mouse VEGF antibodies. The mobile laser indirect ophthalmoscope can serve as a feasible and a reliable alternative method for the CNV induction in a mouse model.

  8. Treatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemia.

    Science.gov (United States)

    Rivera-Barahona, Ana; Alonso-Barroso, Esmeralda; Pérez, Belén; Murphy, Michael P; Richard, Eva; Desviat, Lourdes R

    2017-09-01

    Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model. Here we set out to investigate whether treatment with a mitochondria-targeted antioxidant, MitoQ, or with the natural polyphenol resveratrol, which is reported to have antioxidant and mitochondrial activation properties, could ameliorate the altered redox status and its functional consequences in the PA mouse model. The results show that oral treatment with MitoQ or resveratrol decreases lipid peroxidation and the expression levels of DNA repair enzyme OGG1 in PA mouse liver, as well as inducing tissue-specific changes in the expression of antioxidant enzymes. Notably, treatment decreased the cardiac hypertrophy marker BNP that is found upregulated in the PA mouse heart. Overall, the results provide in vivo evidence to justify more in depth investigations of antioxidants as adjuvant therapy in PA. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Thalidomide-induced limb abnormalities in a humanized CYP3A mouse model.

    Science.gov (United States)

    Kazuki, Yasuhiro; Akita, Masaharu; Kobayashi, Kaoru; Osaki, Mitsuhiko; Satoh, Daisuke; Ohta, Ryo; Abe, Satoshi; Takehara, Shoko; Kazuki, Kanako; Yamazaki, Hiroshi; Kamataki, Tetsuya; Oshimura, Mitsuo

    2016-02-23

    Thalidomide is a teratogen in humans but not in rodents. It causes multiple birth defects including malformations of limbs, ears, and other organs. However, the species-specific mechanism of thalidomide teratogenicity is not completely understood. Reproduction of the human teratogenicity of thalidomide in rodents has previously failed because of the lack of a model reflecting human drug metabolism. In addition, because the maternal metabolic effect cannot be eliminated, the migration of unchanged thalidomide to embryos is suppressed, and the metabolic activation is insufficient to develop teratogenicity. Previously, we generated transchromosomic mice containing a human cytochrome P450 (CYP) 3A cluster in which the endogenous mouse Cyp3a genes were deleted. Here, we determined whether human CYP3A or mouse Cyp3a enzyme expression was related to the species difference in a whole embryo culture system using humanized CYP3A mouse embryos. Thalidomide-treated embryos with the human CYP3A gene cluster showed limb abnormalities, and human CYP3A was expressed in the placenta, suggesting that human CYP3A in the placenta may contribute to the teratogenicity of thalidomide. These data suggest that the humanized CYP3A mouse is a useful model to predict embryonic toxicity in humans.

  10. Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology

    Directory of Open Access Journals (Sweden)

    Marten Szibor

    2017-02-01

    Full Text Available Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.

  11. A novel conditional Sgsh knockout mouse model recapitulates phenotypic and neuropathic deficits of Sanfilippo syndrome.

    Science.gov (United States)

    Lau, Adeline A; King, Barbara M; Thorsen, Carly L; Hassiotis, Sofia; Beard, Helen; Trim, Paul J; Whyte, Lauren S; Tamang, Sarah J; Duplock, Stephen K; Snel, Marten F; Hopwood, John J; Hemsley, Kim M

    2017-09-01

    Mucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal storage disorder caused by a deficiency of the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), involved in the catabolism of heparan sulfate. The clinical spectrum is broad and the age of symptom onset and the degree of preservation of cognitive and motor functions appears greatly influenced by genotype. To explore this further, we generated a conditional knockout (Sgsh KO ) mouse model with ubiquitous Sgsh deletion, and compared the clinical and pathological phenotype with that of the spontaneous Sgsh D31N MPS-IIIA mouse model. Phenotypic deficits were noted in Sgsh KO mice prior to Sgsh D31N mice, however these outcomes did not correlate with any shift in the time of appearance nor rate of accumulation of primary (heparan sulfate) or secondary substrates (GM2/GM3 gangliosides). Other disease lesions (elevations in lysosomal integral membrane protein-II expression, reactive astrocytosis and appearance of ubiquitin-positive inclusions) were also comparable between affected mouse strains. This suggests that gross substrate storage and these neuropathological markers are neither primary determinants, nor good biomarkers/indicators of symptom generation, confirming similar observations made recently in MPS-IIIA patients. The Sgsh KO mouse will be a useful tool for elucidation of the neurological basis of disease and assessment of the clinical efficacy of new treatments for Sanfilippo syndrome.

  12. Animal models of gastrointestinal and liver diseases. New mouse models for studying dietary prevention of colorectal cancer

    Science.gov (United States)

    2014-01-01

    Colorectal cancer is a heterogeneous disease that is one of the major causes of cancer death in the U.S. There is evidence that lifestyle factors like diet can modulate the course of this disease. Demonstrating the benefit and mechanism of action of dietary interventions against colon cancer will require studies in preclinical models. Many mouse models have been developed to study colon cancer but no single model can reflect all types of colon cancer in terms of molecular etiology. In addition, many models develop only low-grade cancers and are confounded by development of the disease outside of the colon. This review will discuss how mice can be used to model human colon cancer and it will describe a variety of new mouse models that develop colon-restricted cancer as well as more advanced phenotypes for studies of late-state disease. PMID:24875098

  13. Diabetic nephropathy in a nonobese mouse model of type 2 diabetes mellitus.

    Science.gov (United States)

    Mallipattu, Sandeep K; Gallagher, Emily J; LeRoith, Derek; Liu, Ruijie; Mehrotra, Anita; Horne, Sylvia J; Chuang, Peter Y; Yang, Vincent W; He, John C

    2014-05-01

    A large body of research has contributed to our understanding of the pathophysiology of diabetic nephropathy. Yet, many questions remain regarding the progression of a disease that accounts for nearly half the patients entering dialysis yearly. Several murine models of diabetic nephropathy secondary to Type 2 diabetes mellitus (T2DM) do exist, and some are more representative than others, but all have limitations. In this study, we aimed to identify a new mouse model of diabetic nephropathy secondary to T2DM in a previously described T2DM model, the MKR (MCK-KR-hIGF-IR) mouse. In this mouse model, T2DM develops as a result of functional inactivation of insulin-like growth factor-1 receptor (IGF-1R) in the skeletal muscle. These mice are lean, with marked insulin resistance, hyperinsulinemia, hyperglycemia, and dyslipidemia and thus are representative of nonobese human T2DM. We show that the MKR mice, when under stress (high-fat diet or unilateral nephrectomy), develop progressive diabetic nephropathy with marked albuminuria and meet the histopathological criteria as defined by the Animal Models of Diabetic Complications Consortium. Finally, these MKR mice are fertile and are on a common background strain, making it a novel model to study the progression of diabetic nephropathy.

  14. Assessment of Th17/Treg cells and Th cytokines in an improved immune thrombocytopenia mouse model.

    Science.gov (United States)

    Zhang, Guoyang; Zhang, Ping; Liu, Hongyun; Liu, Xiaoyan; Xie, Shuangfeng; Wang, Xiuju; Wu, Yudan; Chang, Jianxing; Ma, Liping

    2017-09-01

    The improved passive immune thrombocytopenia (ITP) mouse model has been extensively utilized for the study of ITP. However, how closely this model matches the human inflammation state and immune background is unclear. Our study aimed to explore the profile of Th cytokines and Th17/Treg cells in the model. We induced the ITP mouse model by dose-escalation injection of MWReg30. The serum levels of cytokines (IFN-γ, IL-2, IL-4, IL-10, IL-17A, and TGF-β1) were measured by enzyme-linked immunosorbent assay and the frequency of Th17 and Treg cells was measured by flow cytometry. The mRNA expression of Foxp3 and RORrt was measured by real-time PCR. The serum levels of cytokines IFN-γ, TGF-β1, IL-4, and IL-10 were significantly lower in ITP mice. The secretion of serum proinflammatory cytokines IL-2 and IL-17A and the percentage of Th17 cells showed no statistically significant increase. In ITP mice the frequency of Treg cells and mRNA expression of Foxp3 was significantly lower in splenocytes. Our data suggest that the improved passive ITP mouse model does not mimic the autoimmune inflammatory process of human ITP. Compared with human ITP, this model has a similar change in frequency of Treg cells, which may directly or indirectly result from antibody-mediated platelet destruction due to attenuated release of TGF-β.

  15. The Cinderella effect: searching for the best fit between mouse models and human diseases.

    Science.gov (United States)

    Sundberg, John P; Roopenian, Derry C; Liu, Edison T; Schofield, Paul N

    2013-11-01

    A recent publication questions the suitability of mice as a model for the human inflammatory response and has fueled the continuing debate about the suitability of mice as models for human disease. We discuss recent advances in disease modeling using mice, and the genetic factors that need to be considered when trying to recapitulate aspects of human disease. Failure to appreciate the important differences between human and mouse biology and genetics underlying attempts to generate faithful models frequently leads to poor outcomes. Closely coordinated human and model organism studies are essential to provide traction for translational research.

  16. Rate equation model of phototransduction into the membranous disks of mouse rod cells

    CERN Document Server

    Takamoto, Rei; Awazu, Akinori

    2015-01-01

    A theoretical model was developed to investigate the rod phototransduction process in the mouse. In particular, we explored the biochemical reactions of several chemical components that contribute to the signaling process into/around the membranous disks in the outer segments of the rod cells. We constructed a rate equation model incorporating the molecular crowding effects of rhodopsin according to experimental results, which may hinder the diffusion of molecules on the disk mem- brane. The present model could effectively reproduce and explain the mechanisms of the following phenomena observed in experiments. First, the activations and relaxation of the wild-type mouse rod cell progressed more slowly than those of mutant cells containing half the amount of rhodopsin on the disk membrane. Second, the strong photoactivated state of the cell was sustained for a longer period when the light stimuli were strong. Finally, the lifetime of photoactivation exhibited a logarithmic increase with increasing light streng...

  17. An improved reprogrammable mouse model harbouring the reverse tetracycline-controlled transcriptional transactivator 3

    Directory of Open Access Journals (Sweden)

    S. Alaei

    2016-07-01

    Full Text Available Reprogrammable mouse models engineered to conditionally express Oct-4, Klf-4, Sox-2 and c-Myc (OKSM have been instrumental in dissecting molecular events underpinning the generation of induced pluripotent stem cells. However, until now these models have been reported in the context of the m2 reverse tetracycline-controlled transactivator, which results in low reprogramming efficiency and consequently limits the number of reprogramming intermediates that can be isolated for downstream profiling. Here, we describe an improved OKSM mouse model in the context of the reverse tetracycline-controlled transactivator 3 with enhanced reprogramming efficiency (>9-fold and increased numbers of reprogramming intermediate cells albeit with similar kinetics, which we believe will facilitate mechanistic studies of the reprogramming process.

  18. Cognitive and pharmacological insights from the Ts65Dn mouse model of Down syndrome.

    Science.gov (United States)

    Ruparelia, Aarti; Pearn, Matthew L; Mobley, William C

    2012-10-01

    Down syndrome (DS) is a multi-faceted condition resulting in the most common genetic form of intellectual disability. Mouse models of DS, especially the Ts65Dn model, have been pivotal in furthering our understanding of the genetic, molecular and neurobiological mechanisms that underlie learning and memory impairments in DS. Cognitive and pharmacological insights from the Ts65Dn mouse model have led to remarkable translational progress in the development of therapeutic targets and in the emergence of DS clinical trials. Unravelling the pathogenic role of trisomic genes on human chromosome 21 and the genotype-phenotype relationship still remains a pertinent goal for tackling cognitive deficits in DS. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Partial corrosion casting to assess cochlear vasculature in mouse models of presbycusis and CMV infection.

    Science.gov (United States)

    Carraro, Mattia; Park, Albert H; Harrison, Robert V

    2016-02-01

    Some forms of sensorineural hearing loss involve damage or degenerative changes to the stria vascularis and/or other vascular structures in the cochlea. In animal models, many methods for anatomical assessment of cochlear vasculature exist, each with advantages and limitations. One methodology, corrosion casting, has proved useful in some species, however in the mouse model this technique is difficult to achieve because digestion of non vascular tissue results in collapse of the delicate cast specimen. We have developed a partial corrosion cast method that allows visualization of vasculature along much of the cochlear length but maintains some structural integrity of the specimen. We provide a detailed step-by-step description of this novel technique. We give some illustrative examples of the use of the method in mouse models of presbycusis and cytomegalovirus (CMV) infection. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Insights into synaptic function from mouse models of human cognitive disorders.

    Science.gov (United States)

    Banko, Jessica L; Trotter, Justin; Weeber, Edwin J

    2011-01-01

    Modern approaches to the investigation of the molecular mechanisms underlying human cognitive disease often include multidisciplinary examination of animal models engineered with specific mutations that spatially and temporally restrict expression of a gene of interest. This approach not only makes possible the development of animal models that demonstrate phenotypic similarities to their respective human disorders, but has also allowed for significant progress towards understanding the processes that mediate synaptic function and memory formation in the nondiseased state. Examples of successful mouse models where genetic manipulation of the mouse resulted in recapitulation of the symptomatology of the human disorder and was used to significantly expand our understanding of the molecular mechanisms underlying normal synaptic plasticity and memory formation are discussed in this article. These studies have broadened our knowledge of several signal transduction cascades that function throughout life to mediate synaptic physiology. Defining these events is key for developing therapies to address disorders of cognitive ability.

  1. Mouse models of acute and chronic hepacivirus infection

    DEFF Research Database (Denmark)

    Billerbeck, Eva; Wolfisberg, Raphael; Fahnøe, Ulrik

    2017-01-01

    An estimated 71 million people worldwide are infected with hepatitis C virus (HCV). The lack of small-animal models has impeded studies of antiviral immune mechanisms. Here we show that an HCV-related hepacivirus discovered in Norway rats can establish high-titer hepatotropic infections in labora......An estimated 71 million people worldwide are infected with hepatitis C virus (HCV). The lack of small-animal models has impeded studies of antiviral immune mechanisms. Here we show that an HCV-related hepacivirus discovered in Norway rats can establish high-titer hepatotropic infections...

  2. Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

    Science.gov (United States)

    Zuberi, Aamir; Lutz, Cathleen

    2016-12-01

    The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling systems

  3. MicroRNAs and Induced Pluripotent Stem Cells for Human Disease Mouse Modeling

    Directory of Open Access Journals (Sweden)

    Chingiz Underbayev

    2012-01-01

    Full Text Available Human disease animal models are absolutely invaluable tools for our understanding of mechanisms involved in both physiological and pathological processes. By studying various genetic abnormalities in these organisms we can get a better insight into potential candidate genes responsible for human disease development. To this point a mouse represents one of the most used and convenient species for human disease modeling. Hundreds if not thousands of inbred, congenic, and transgenic mouse models have been created and are now extensively utilized in the research labs worldwide. Importantly, pluripotent stem cells play a significant role in developing new genetically engineered mice with the desired human disease-like phenotype. Induced pluripotent stem (iPS cells which represent reprogramming of somatic cells into pluripotent stem cells represent a significant advancement in research armament. The novel application of microRNA manipulation both in the generation of iPS cells and subsequent lineage-directed differentiation is discussed. Potential applications of induced pluripotent stem cell—a relatively new type of pluripotent stem cells—for human disease modeling by employing human iPS cells derived from normal and diseased somatic cells and iPS cells derived from mouse models of human disease may lead to uncovering of disease mechanisms and novel therapies.

  4. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Francis Richard W

    2010-04-01

    Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

  5. Quantification of Lung Metastases from In Vivo Mouse Models

    DEFF Research Database (Denmark)

    Chang, Joan; Erler, Janine T

    2016-01-01

    Cancer research has made significant progress in terms of understanding and targeting primary tumors; however, the challenge remains for the successful treatment of metastatic cancers. This highlights the importance to use in vivo models to study the metastatic process, as well as for preclinical...

  6. Molecular Alterations in a Mouse Cardiac Model of Friedreich Ataxia

    DEFF Research Database (Denmark)

    Anzovino, Amy; Chiang, Shannon; Brown, Bronwyn E

    2017-01-01

    Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the antioxidant response. However, studies in models of Friedreich ataxia, a neurodegenerative and cardiodegenerative disease associated with oxidative stress, reported decreased Nrf2 expression attributable to unknown...

  7. A genetically humanized mouse model for hepatitis C virus infection.

    NARCIS (Netherlands)

    Dorner, M.; Horwitz, J.A.; Robbins, J.B.; Barry, W.T.; Feng, Q.; Mu, K.; Jones, C.T.; Schoggins, J.W.; Catanese, M.T.; Burton, D.R.; Law, M.; Rice, C.M.; Ploss, A.

    2011-01-01

    Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with

  8. Mouse model in food allergy: dynamic determination of shrimp ...

    African Journals Online (AJOL)

    ... the method could continuously reflect the variation of allergic symptom and actualize dynamic determination of shrimp allergenicity. Furthermore, it is feasible, sensitive and repeatable. The approach will provide some valuable reference for identifying allergenicity of novel food proteins by using animal model in the future.

  9. Development of a metastatic fluorescent Lewis Lung carcinoma mouse model

    DEFF Research Database (Denmark)

    Rask, Lene; Fregil, Marianne; Høgdall, Estrid

    2013-01-01

    models. To examine the mechanisms involved in tumor metastasis, we first generated a stably transfected Lewis Lung carcinoma cell line expressing a far-red fluorescent protein, called Katushka. After in vivo growth in syngeneic mice, two fluorescent Lewis Lung cancer subpopulations were isolated from...

  10. FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia.

    Directory of Open Access Journals (Sweden)

    Yogesh K Chutake

    Full Text Available Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues.The humanized mouse model of Friedreich ataxia (YG8sR, which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R. We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse.Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.

  11. Novel mouse model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis

    DEFF Research Database (Denmark)

    Hoffmann, Nadine; Rasmussen, Thomas Bovbjerg; Jensen, Peter Østrup

    2005-01-01

    Pseudomonas aeruginosa causes a chronic infection in the lungs of cystic fibrosis (CF) patients by establishing an alginate-containing biofilm. The infection has been studied in several animal models; however, most of the models required artificial embedding of the bacteria. We present here a new...... pulmonary mouse model without artificial embedding. The model is based on a stable mucoid CF sputum isolate (NH57388A) with hyperproduction of alginate due to a deletion in mucA and functional N-acylhomoserine lactone (AHL)-based quorum-sensing systems. Chronic lung infection could be established in both CF...

  12. Organoid Models of Human and Mouse Ductal Pancreatic Cancer

    Science.gov (United States)

    Boj, Sylvia F.; Hwang, Chang-Il; Baker, Lindsey A.; Chio, Iok In Christine; Engle, Dannielle D.; Corbo, Vincenzo; Jager, Myrthe; Ponz-Sarvise, Mariano; Tiriac, Hervé; Spector, Mona S.; Gracanin, Ana; Oni, Tobiloba; Yu, Kenneth H.; van Boxtel, Ruben; Huch, Meritxell; Rivera, Keith D.; Wilson, John P.; Feigin, Michael E.; Öhlund, Daniel; Handly-Santana, Abram; Ardito-Abraham, Christine M.; Ludwig, Michael; Elyada, Ela; Alagesan, Brinda; Biffi, Giulia; Yordanov, Georgi N.; Delcuze, Bethany; Creighton, Brianna; Wright, Kevin; Park, Youngkyu; Morsink, Folkert H.M.; Molenaar, I. Quintus; Borel Rinkes, Inne H.; Cuppen, Edwin; Hao, Yuan; Jin, Ying; Nijman, Isaac J.; Iacobuzio-Donahue, Christine; Leach, Steven D.; Pappin, Darryl J.; Hammell, Molly; Klimstra, David S.; Basturk, Olca; Hruban, Ralph H.; Offerhaus, George Johan; Vries, Robert G.J.; Clevers, Hans; Tuveson, David A.

    2015-01-01

    SUMMARY Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation and exhibit ductal- and disease stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy. PMID:25557080

  13. Analgesic effects of NB001 on mouse models of arthralgia

    OpenAIRE

    Tian, Zhen; Wang, Dong-sheng; Wang, Xin-shang; Tian, Jiao; Han, Jing; Guo, Yan-yan; Feng, Bin; Zhang, Nan; Zhao, Ming-gao; Liu, Shui-bing

    2015-01-01

    Our previous studies have demonstrated the critical roles of calcium-stimulated adenylyl cyclase 1 (AC1) in the central nervous system in chronic pain. In the present study, we examined the analgesic effects of NB001, a selective inhibitor of AC1, on animal models of ankle joint arthritis and knee joint arthritis induced by complete Freund’s adjuvant injection. NB001 treatment had no effect on joint edema, stiffness, and joint destruction. Furthermore, the treatment failed to attenuate the di...

  14. Modelling human myoblasts survival upon xenotransplantation into immunodeficient mouse muscle.

    Science.gov (United States)

    Praud, Christophe; Vauchez, Karine; Zongo, Pascal; Vilquin, Jean-Thomas

    2018-03-15

    Cell transplantation has been challenged in several clinical indications of genetic or acquired muscular diseases, but therapeutic success were mitigated. To understand and improve the yields of tissue regeneration, we aimed at modelling the fate of CD56-positive human myoblasts after transplantation. Using immunodeficient severe combined immunodeficiency (SCID) mice as recipients, we assessed the survival, integration and satellite cell niche occupancy of human myoblasts by a triple immunohistochemical labelling of laminin, dystrophin and human lamin A/C. The counts were integrated into a classical mathematical decline equation. After injection, human cells were essentially located in the endomysium, then they disappeared progressively from D0 to D28. The final number of integrated human nuclei was grossly determined at D2 after injection, suggesting that no more efficient fusion between donor myoblasts and host fibers occurs after the resolution of the local damages created by needle insertion. Almost 1% of implanted human cells occupied a satellite-like cell niche. Our mathematical model validated by histological counting provided a reliable quantitative estimate of human myoblast survival and/or incorporation into SCID muscle fibers. Informations brought by histological labelling and this mathematical model are complementary. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. A Susceptible Mouse Model for Zika Virus Infection.

    Directory of Open Access Journals (Sweden)

    Stuart D Dowall

    2016-05-01

    Full Text Available Zika virus (ZIKV is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129 mice and the parent strain (129Sv/Ev after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals.

  16. A Susceptible Mouse Model for Zika Virus Infection.

    Science.gov (United States)

    Dowall, Stuart D; Graham, Victoria A; Rayner, Emma; Atkinson, Barry; Hall, Graham; Watson, Robert J; Bosworth, Andrew; Bonney, Laura C; Kitchen, Samantha; Hewson, Roger

    2016-05-01

    Zika virus (ZIKV) is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129) mice and the parent strain (129Sv/Ev) after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals.

  17. Mouse models for pseudoxanthoma elasticum: genetic and dietary modulation of the ectopic mineralization phenotypes.

    Directory of Open Access Journals (Sweden)

    Qiaoli Li

    Full Text Available Pseudoxanthoma elasticum (PXE, a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6(-/- recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6(-/- mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904 in the Abcc6 gene, which resulted in out-of-frame splicing and marked reduction in ABCC6 protein expression in the liver of these mice. The same polymorphism is present in two additional mouse strains, DBA/2J and C3H/HeJ, with similar reduction in Abcc6 protein levels, yet these mice did not demonstrate tissue mineralization when kept on standard rodent diet. However, all four mouse strains, when placed on experimental diet enriched in phosphate and low in magnesium, developed extensive ectopic mineralization. These results indicate that the genetic background of mice and the mineral composition of their diet can profoundly modulate the ectopic mineralization process predicated on mutations in the Abcc6 gene. These mice provide novel model systems to study the pathomechanisms and the reasons for strain background on phenotypic variability of PXE.

  18. Abnormalities in the tricarboxylic Acid cycle in Huntington disease and in a Huntington disease mouse model.

    Science.gov (United States)

    Naseri, Nima N; Xu, Hui; Bonica, Joseph; Vonsattel, Jean Paul G; Cortes, Etty P; Park, Larry C; Arjomand, Jamshid; Gibson, Gary E

    2015-06-01

    Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease, and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase complex (PDHC) and the tricarboxylic acid (TCA) cycle, may contribute to these deficits. Here, activities for these enzymes and select protein levels were measured in human postmortem cortex and in striatum and cortex of an HD mouse model (Q175); mRNA levels encoding for these enzymes were also measured in the Q175 mouse cortex. The activities of PDHC and nearly all of the TCA cycle enzymes were dramatically lower (-50% to 90%) in humans than in mice. The activity of succinate dehydrogenase increased with HD in human (35%) and mouse (23%) cortex. No other changes were detected in the human HD cortex or mouse striatum. In Q175 cortex, there were increased activities of PDHC (+12%) and aconitase (+32%). Increased mRNA levels for succinyl thiokinase (+88%) and isocitrate dehydrogenase (+64%) suggested an upregulation of the TCA cycle. These patterns of change differ from those reported in other diseases, which may offer unique metabolic therapeutic opportunities for HD patients.

  19. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model.

    Science.gov (United States)

    Leinenga, Gerhard; Götz, Jürgen

    2015-03-11

    Amyloid-β (Aβ) peptide has been implicated in the pathogenesis of Alzheimer's disease (AD). We present a nonpharmacological approach for removing Aβ and restoring memory function in a mouse model of AD in which Aβ is deposited in the brain. We used repeated scanning ultrasound (SUS) treatments of the mouse brain to remove Aβ, without the need for any additional therapeutic agent such as anti-Aβ antibody. Spinning disk confocal microscopy and high-resolution three-dimensional reconstruction revealed extensive internalization of Aβ into the lysosomes of activated microglia in mouse brains subjected to SUS, with no concomitant increase observed in the number of microglia. Plaque burden was reduced in SUS-treated AD mice compared to sham-treated animals, and cleared plaques were observed in 75% of SUS-treated mice. Treated AD mice also displayed improved performance on three memory tasks: the Y-maze, the novel object recognition test, and the active place avoidance task. Our findings suggest that repeated SUS is useful for removing Aβ in the mouse brain without causing overt damage, and should be explored further as a noninvasive method with therapeutic potential in AD. Copyright © 2015, American Association for the Advancement of Science.

  20. A mouse model for binge-like sucrose overconsumption: Contribution of enhanced motivation for sweetener consumption.

    Science.gov (United States)

    Yasoshima, Yasunobu; Shimura, Tsuyoshi

    2015-01-01

    Behavioral and neural features of binge-like sugar overconsumption have been studied using rat models. However, few mouse models are available to examine the interaction between neural and genetic underpinnings of bingeing. In the present study, we first aim to establish a simple mouse model of binge-like sucrose overconsumption using daytime limited access training in food-restricted male mice. Trained mice received 4-h limited access to both 0.5M sucrose solution and chow for 10 days. Three control groups received (1) 4-h sucrose and 20-h chow access, (2) 20-h sucrose and 4-h, or (3) 20-h chow access, respectively. Only the trained group showed progressively increased sucrose consumption during brief periods of time and developed binge-like excessive behavior. Next, we examined whether the present mouse model mimicked a human feature of binge eating known as "eating when not physically hungry." Trained mice consumed significantly more sucrose or non-caloric sweetener (saccharin) during post-training days even after they nocturnally consumed substantial chow prior to daytime sweetener access. In other trained groups, both a systemic administration of glucose and substantial chow consumption prior to the daytime limited sucrose access failed to reduce binge-like sucrose overconsumption. Our results suggest that even when caloric consumption is not necessarily required, limited access training shapes and triggers binge-like overconsumption of sweetened solution in trained mice. The binge-like behavior in trained mice may be mainly due to enhanced hedonic motivation for the sweetener's taste. The present study suggests that our mouse model for binge-like sugar overconsumption may mimic some human features of binge eating and can be used to investigate the roles of neural and genetic mechanisms in binge-like overconsumption of sweetened substances in the absence of physical hunger. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation.

    Directory of Open Access Journals (Sweden)

    Sian E Piret

    Full Text Available Chronic kidney disease (CKD is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8 Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2 expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the

  2. A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation.

    Science.gov (United States)

    Piret, Sian E; Esapa, Christopher T; Gorvin, Caroline M; Head, Rosie; Loh, Nellie Y; Devuyst, Olivier; Thomas, Gethin; Brown, Steve D M; Brown, Matthew; Croucher, Peter; Cox, Roger; Thakker, Rajesh V

    2012-01-01

    Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8 Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH

  3. A Mouse Model of Early-Onset Renal Failure Due to a Xanthine Dehydrogenase Nonsense Mutation

    Science.gov (United States)

    Gorvin, Caroline M.; Head, Rosie; Loh, Nellie Y.; Devuyst, Olivier; Thomas, Gethin; Brown, Steve D. M.; Brown, Matthew; Croucher, Peter; Cox, Roger; Thakker, Rajesh V.

    2012-01-01

    Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH

  4. Development of a mouse model of abdominal cutaneous flaps for breast reconstruction.

    Science.gov (United States)

    Womac, Daniel John; Palanisamy, Arun Prathap; Eslick, Rene; Schimpf, Dennis Kenneth; Chavin, Kenneth David

    2013-01-01

    Autologous tissue transfer, in addition to replacing tissue that was lost during injury or surgery, offers women an excellent option to improve cosmetic appearance and self-confidence following mastectomy due to breast cancer. However, flap necrosis is a complication in obese patients undergoing this procedure. We created a mouse model to study the flap-related complications that leads to decreased flap survival in autologous breast reconstruction. Left superficial inferior epigastric (SIE) pedicle abdominal-cutaneous flaps were elevated in 8 week-old, obese ob/ob male mice and their lean littermates. Flaps were followed by serial photography. Area of flap necrosis was measured at 7 days. Statistical analysis was performed. Necrosis was observed at the distal margin of the flaps, in both lean and obese groups. Lean left SIE flaps (n = 8) had a total area flap necrosis of 9.1% at 7 days whereas obese left SIE flaps (n = 8) had a total area flap necrosis of 45.5% at 7 days. Obese flaps had a statistically significant increase in necrosis compared to the lean flaps, p = 0.001. There was a significant difference between flap survival in lean and obese SIE pedicle flaps in our mouse model. We have developed the first flap model of obesity utilizing the superficial epigastric pedicle in the mouse. This model is optimal for future studies to dissect out mechanisms that lead to the complications related to flap survival for breast reconstruction, especially in obese subjects.

  5. Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research.

    Science.gov (United States)

    Zhou, Ting; Kinney, Marsha C; Scott, Linda M; Zinkel, Sandra S; Rebel, Vivienne I

    2015-08-27

    Much-needed attention has been given of late to diseases specifically associated with an expanding elderly population. Myelodysplastic syndrome (MDS), a hematopoietic stem cell-based blood disease, is one of these. The lack of clear understanding of the molecular mechanisms underlying the pathogenesis of this disease has hampered the development of efficacious therapies, especially in the presence of comorbidities. Mouse models could potentially provide new insights into this disease, although primary human MDS cells grow poorly in xenografted mice. This makes genetically engineered murine models a more attractive proposition, although this approach is not without complications. In particular, it is unclear if or how myelodysplasia (abnormal blood cell morphology), a key MDS feature in humans, presents in murine cells. Here, we evaluate the histopathologic features of wild-type mice and 23 mouse models with verified myelodysplasia. We find that certain features indicative of myelodysplasia in humans, such as Howell-Jolly bodies and low neutrophilic granularity, are commonplace in healthy mice, whereas other features are similarly abnormal in humans and mice. Quantitative hematopoietic parameters, such as blood cell counts, are required to distinguish between MDS and related diseases. We provide data that mouse models of MDS can be genetically engineered and faithfully recapitulate human disease. © 2015 by The American Society of Hematology.

  6. Humanized mouse as an appropriate model for accelerated global HIV research and vaccine development: current trend.

    Science.gov (United States)

    Ibeh, Bartholomew Okechukwu; Furuta, Yasuhide; Habu, Josiah Bitrus; Ogbadu, Lucy

    2016-09-23

    Humanized mouse models currently have seen improved development and have received wide applications. Its usefulness is observed in cell and tissue transplant involving basic and applied human disease research. In this article, the development of a new generation of humanized mice was discussed as well as their relevant application in HIV disease. Furthermore, current techniques employed to overcome the initial limitations of mouse model were reviewed. Highly immunodeficient mice which support cell and tissue differentiation and do not reject xenografts are indispensable for generating additional appropriate models useful in disease study, this phenomenom deserves emphases, scientific highlight and a definitive research focus. Since the early 2000s, a series of immunodeficient mice appropriate for generating humanized mice has been successively developed by introducing the IL-2Rγnull gene (e.g. NOD/SCID/γcnull and Rag2nullγcnull mice) through various genomic approaches. These mice were generated by genetically introducing human cytokine genes into NOD/SCID/γcnull and Rag2nullγcnull mouse backgrounds. The application of these techniques serves as a quick and appropriate mechanistic model for basic and therapeutic investigations of known and emerging infections.

  7. Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models

    Science.gov (United States)

    Xu, Jian; Phillips, Andre; Topol, Aaron; Xu, Meiyu; Ononenyi, Chimezie; Foscue, Ethan; Ho, Seok-Man; Baguley, Tyler D.; Carty, Nikisha; Barros, Claudia S.; Müller, Ulrich; Gupta, Sounak; Gochman, Peter A.; Rapoport, Judith; Ellman, Jonathan A.; Pittenger, Christopher; Aronow, Bruce; Nairn, Angus C.; Nestor, Michael W.; Lombroso, Paul J.; Brennand, Kristen J.

    2016-01-01

    The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptors (NMDARs) internalization through dephosphorylation of GluN2B and inactivation of the kinases ERK1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/− knockout mouse model of SZ. Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDA receptors from synaptic membranes and reverses behavioral deficits in Nrg1+/− mice. STEP61 protein is also increased in cortical lysates from the CNS-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ. PMID:27752082

  8. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications.

    Science.gov (United States)

    Sportoletti, P; Varasano, E; Rossi, R; Mupo, A; Tiacci, E; Vassiliou, G; Martelli, M P; Falini, B

    2015-02-01

    Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) mutations displays distinct biological and clinical features that led to its inclusion as a provisional disease entity in the 2008 World Health Organization (WHO) classification of myeloid neoplasms. Studies of the molecular mechanisms underlying the pathogenesis of NPM1-mutated AML have benefited greatly from several mouse models of this leukemia developed over the past few years. Immunocompromised mice xenografted with NPM1-mutated AML served as the first valuable tool for defining the biology of the disease in vivo. Subsequently, genetically engineered mouse models of the NPM1 mutation, including transgenic and knock-in alleles, allowed the generation of mice with a constant genotype and a reproducible phenotype. These models have been critical for investigating the nature of the molecular effects of these mutations, defining the function of leukemic stem cells in NPM1-mutated AML, identifying chemoresistant preleukemic hemopoietic stem cells and unraveling the key molecular events that cooperate with NPM1 mutations to induce AML in vivo. Moreover, they can serve as a platform for the discovery and validation of new antileukemic drugs in vivo. Advances derived from the analysis of these mouse models promise to greatly accelerate the development of new molecularly targeted therapies for patients with NPM1-mutated AML.

  9. Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

    Science.gov (United States)

    Hamlett, Eric D.; Boger, Heather A.; Ledreux, Aurélie; Kelley, Christy M.; Mufson, Elliott J.; Falangola, Maria F.; Guilfoyle, David N.; Nixon, Ralph A.; Patterson, David; Duval, Nathan; Granholm, Ann-Charlotte E.

    2016-01-01

    Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer’s disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review age-related neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration. PMID:26391050

  10. CSF transthyretin neuroprotection in a mouse model of brain ischemia

    DEFF Research Database (Denmark)

    Santos, Sofia Duque; Lambertsen, Kate Lykke; Clausen, Bettina Hjelm

    2010-01-01

    Brain injury caused by ischemia is a major cause of human mortality and physical/cognitive disability worldwide. Experimentally, brain ischemia can be induced surgically by permanent middle cerebral artery occlusion. Using this model, we studied the influence of transthyretin in ischemic stroke....... However, TTR null mice, heterozygous for the heat-shock transcription factor 1 (TTR(-/-) HSF1(+/-) mice), which compromised the stress response, showed a significant increase in cortical infarction, cerebral edema and the microglial-leukocyte response compared with TTR(+/+) HSF1(+/-) mice. Unexpectedly...

  11. Experimental model of occlusal trauma in mouse periodontal tissues.

    OpenAIRE

    Fujii, T; Takaya, T; Mimura, H; Osuga, N; Matsuda, S; Nakano, K

    2014-01-01

    The aim of this study was to establish a model, which can be used to investigate the response of periodontal tissues to excessive occlusal loading in mice by observing histopathological changes. The experiment was performed on ten 7-week-old ddY male mice. Under general anesthesia by intraperitoneal injectionpentobarbital sodium, a micro-plus-screwpin (head part, 1.7mm in diameter, thickness 0.5mm thickness) was screwed into the pulp cavity of the upper-left-first molar. R_mCT images of the e...

  12. Heterogeneity in oligodendroglia: Is it relevant to mouse models and human disease?

    Science.gov (United States)

    Ornelas, Isis M; McLane, Lauren E; Saliu, Aminat; Evangelou, Angelina V; Khandker, Luipa; Wood, Teresa L

    2016-12-01

    There are many lines of evidence indicating that oligodendrocyte progenitor cells and oligodendrocyte populations in the central nervous system (CNS) are heterogeneous based on their developmental origins as well as from morphological and molecular criteria. Whether these distinctions reflect functional heterogeneity is less clear and has been the subject of considerable debate. Recent findings, particularly from knockout mouse models, have provided new evidence for regional variations in myelination phenotypes, particularly between brain and spinal cord. These data raise the possibility that oligodendrocytes in these regions have different functional capacities and/or ability to compensate for loss of a specific gene. The goal of this review is to briefly revisit the evidence for oligodendrocyte heterogeneity and then to present data from transgenic and demyelinating mouse models suggesting functional heterogeneity in myelination, demyelination, and remyelination in the CNS and, finally, to discuss the implications of these findings for human diseases. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. Imaging noradrenergic influence on amyloid pathology in mouse models of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Winkeler, A.; Waerzeggers, Y.; Klose, A.; Monfared, P.; Thomas, A.V.; Jacobs, A.H. [Max Planck Institute for Neurological Research with Klaus-Joachim-Zuelch-Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne, Laboratory for Gene Therapy and Molecular Imaging, Cologne (Germany); Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); Schubert, M. [Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); Heneka, M.T. [Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); University of Muenster, Department of Neurology, Muenster (Germany)

    2008-03-15

    Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers' disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases. (orig.)

  14. The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome.

    Directory of Open Access Journals (Sweden)

    Scott T Kelley

    Full Text Available Women with polycystic ovary syndrome (PCOS have reproductive and metabolic abnormalities that result in an increased risk of infertility, diabetes and cardiovascular disease. The large intestine contains a complex community of microorganisms (the gut microbiome that is dysregulated in humans with obesity and type 2 diabetes. Using a letrozole-induced PCOS mouse model, we demonstrated significant diet-independent changes in the gut microbial community, suggesting that gut microbiome dysbiosis may also occur in PCOS women. Letrozole treatment was associated with a time-dependent shift in the gut microbiome and a substantial reduction in overall species and phylogenetic richness. Letrozole treatment also correlated with significant changes in the abundance of specific Bacteroidetes and Firmicutes previously implicated in other mouse models of metabolic disease in a time-dependent manner. Our results suggest that the hyperandrogenemia observed in PCOS may significantly alter the gut microbiome independently of diet.

  15. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Steve P. Crampton

    2014-09-01

    Full Text Available Systemic lupus erythematosus (SLE represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.

  16. Cilia/Ift protein and motor-related bone diseases and mouse models

    Science.gov (United States)

    Yuan, Xue; Yang, Shuying

    2015-01-01

    Primary cilia are essential cellular organelles projecting from the cell surface to sense and transduce developmental signaling. They are tiny but have complicated structures containing microtubule (MT)-based internal structures (the axoneme) and mother centriole formed basal body. Intraflagellar transport (Ift) operated by Ift proteins and motors are indispensable for cilia formation and function. Mutations in Ift proteins or Ift motors cause various human diseases, some of which have severe bone defects. Over the last few decades, major advances have occurred in understanding the roles of these proteins and cilia in bone development and remodeling by examining cilia/Ift protein-related human diseases and establishing mouse transgenic models. In this review, we describe current advances in the understanding of the cilia/Ift structure and function. We further summarize cilia/Ift-related human diseases and current mouse models with an emphasis on bone-related phenotypes, cilia morphology, and signaling pathways. PMID:25553465

  17. Fucoidan Extracted from Fucus evanescens Prevents Endotoxin-Induced Damage in a Mouse Model of Endotoxemia

    Directory of Open Access Journals (Sweden)

    Tatyana A. Kuznetsova

    2014-01-01

    Full Text Available An important problem of treating patients with endotoxemia is to find drugs to reduce the negative effects of endotoxin on the organism. We tested fucoidan (sulfated polysaccharide from the brown alga Fucus evanescens as a potential drug in a mouse model of endotoxemia inducted by lipopolysaccharide (LPS. The survival time of mice injected with LPS increased under fucoidan treatment compared with the group of mice injected with LPS only. The preventive administration of fucoidan to mice with endotoxemia resulted in inhibition of increased levels of proinflammatory cytokines (TNFα and IL-6, as well as decreasing of the processes of hypercoagulability. The parenteral or per os administration of fucoidan resulted in decreasing the degree of microcirculatory disorders and secondary dystrophic-destructive changes in parenchymal organs of mice with endotoxemia. Taken together, these results demonstrate that fucoidan prevents endotoxin-induced damage in a mouse model of endotoxemia and increases the mice’s resistance to LPS.

  18. Fucoidan extracted from Fucus evanescens prevents endotoxin-induced damage in a mouse model of endotoxemia.

    Science.gov (United States)

    Kuznetsova, Tatyana A; Besednova, Natalya N; Somova, Larisa M; Plekhova, Natalya G

    2014-01-31

    An important problem of treating patients with endotoxemia is to find drugs to reduce the negative effects of endotoxin on the organism. We tested fucoidan (sulfated polysaccharide) from the brown alga Fucus evanescens as a potential drug in a mouse model of endotoxemia inducted by lipopolysaccharide (LPS). The survival time of mice injected with LPS increased under fucoidan treatment compared with the group of mice injected with LPS only. The preventive administration of fucoidan to mice with endotoxemia resulted in inhibition of increased levels of proinflammatory cytokines (TNFα and IL-6), as well as decreasing of the processes of hypercoagulability. The parenteral or per os administration of fucoidan resulted in decreasing the degree of microcirculatory disorders and secondary dystrophic-destructive changes in parenchymal organs of mice with endotoxemia. Taken together, these results demonstrate that fucoidan prevents endotoxin-induced damage in a mouse model of endotoxemia and increases the mice's resistance to LPS.

  19. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    Science.gov (United States)

    Crampton, Steve P.; Morawski, Peter A.; Bolland, Silvia

    2014-01-01

    Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease. PMID:25147296

  20. Whole-brain ex-vivo quantitative MRI of the cuprizone mouse model

    Directory of Open Access Journals (Sweden)

    Tobias C. Wood

    2016-11-01

    Full Text Available Myelin is a critical component of the nervous system and a major contributor to contrast in Magnetic Resonance (MR images. However, the precise contribution of myelination to multiple MR modalities is still under debate. The cuprizone mouse is a well-established model of demyelination that has been used in several MR studies, but these have often imaged only a single slice and analysed a small region of interest in the corpus callosum. We imaged and analyzed the whole brain of the cuprizone mouse ex-vivo using high-resolution quantitative MR methods (multi-component relaxometry, Diffusion Tensor Imaging (DTI and morphometry and found changes in multiple regions, including the corpus callosum, cerebellum, thalamus and hippocampus. The presence of inflammation, confirmed with histology, presents difficulties in isolating the sensitivity and specificity of these MR methods to demyelination using this model.

  1. An overview of loco-regional treatments in patients and mouse models for hepatocellular carcinoma.

    Science.gov (United States)

    Bimonte, Sabrina; Barbieri, Antonio; Palaia, Raffaele; Leongito, Maddalena; Albino, Vittorio; Piccirillo, Mauro; Arra, Claudio; Izzo, Francesco

    2015-01-01

    Hepatocellular carcinoma is a highly aggressive malignancy and is the third leading cause of cancer-related deaths worldwide. Although surgery is currently considered the most effective curative treatment for this type of cancer, it is note that most of patients have a poor prognosis due to chemioresistence and tumor recurrence. Loco-regional therapies, including radiofrequency ablation, surgical resection and transcatheter arterial chemoembolization play a major role in the clinical management of hepatocellular carcinoma. In order to improve the treatment outcome of patients diagnosed with this disease, several in vivo studies by using different techniques on cancer mouse models have been performed. This review will focus on the latest papers on the efficacy of loco-regional therapy and combined treatments in patients and mouse models of hepatocellular carcinoma.

  2. Chronic Hypertension Leads to Neurodegeneration in the TgSwDI Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Kruyer, Anna; Soplop, Nadine; Strickland, Sidney; Norris, Erin H

    2015-07-01

    Numerous epidemiological studies link vascular disorders, such as hypertension, diabetes mellitus, and stroke, with Alzheimer's disease (AD). Hypertension, specifically, is an important modifiable risk factor for late-onset AD. To examine the link between midlife hypertension and the onset of AD later in life, we chemically induced chronic hypertension in the TgSwDI mouse model of AD in early adulthood. Hypertension accelerated cognitive deficits in the Barnes maze test (Phypertension induced hippocampal neurodegeneration at an early age in this mouse line (43% reduction in the dorsal subiculum; P<0.05), establishing this as a useful research model of AD with mixed vascular and amyloid pathologies. © 2015 American Heart Association, Inc.

  3. Mouse model of alloimmune-induced vascular rejection and transplant arteriosclerosis.

    Science.gov (United States)

    Enns, Winnie; von Rossum, Anna; Choy, Jonathan

    2015-05-17

    Vascular rejection that leads to transplant arteriosclerosis (TA) is the leading representation of chronic heart transplant failure. In TA, the immune system of the recipient causes damage of the arterial wall and dysfunction of endothelial cells and smooth muscle cells. This triggers a pathological repair response that is characterized by intimal thickening and luminal occlusion. Understanding the mechanisms by which the immune system causes vasculature rejection and TA may inform the development of novel ways to manage graft failure. Here, we describe a mouse aortic interposition model that can be used to study the pathogenic mechanisms of vascular rejection and TA. The model involves grafting of an aortic segment from a donor animal into an allogeneic recipient. Rejection of the artery segment involves alloimmune reactions and results in arterial changes that resemble vascular rejection. The basic technical approach we describe can be used with different mouse strains and targeted interventions to answer specific questions related to vascular rejection and TA.

  4. Transgenic Mouse Models for Alcohol Metabolism, Toxicity and Cancer

    Science.gov (United States)

    Heit, Claire; Dong, Hongbin; Chen, Ying; Shah, Yatrik M.; Thompson, David C.; Vasiliou, Vasilis

    2015-01-01

    Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remains to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol metabolizing enzymes and GSH synthesizing enzymes and their relevance to alcohol research. PMID:25427919

  5. Transgenic mouse models for alcohol metabolism, toxicity, and cancer.

    Science.gov (United States)

    Heit, Claire; Dong, Hongbin; Chen, Ying; Shah, Yatrik M; Thompson, David C; Vasiliou, Vasilis

    2015-01-01

    Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remain to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol-metabolizing enzymes and GSH-synthesizing enzymes and their relevance to alcohol research.

  6. An In Vivo Mouse Model for Human Prostate Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Aaron M. Havens

    2008-04-01

    Full Text Available We developed a sensitive real-time polymerase chain reaction (QPCR assay that allows us to track early lodging/homing events in vivo. We used this technology to develop a metastasis assay of human prostate cancer (PCa growth in severe combined immunodeficient mice. For this purpose, marked human PCa cell lines were implanted subcutaneously or in the prostate (orthotopically of severe combined immunodeficient mice as models of primary tumors. Mice were then sacrificed at various time points, and distant tissues were investigated for the presence of metastatic cells. At 3 weeks, a number of tissues were recovered and evaluated by QPCR for the presence of metastatic cells. The data demonstrate that several PCa cell lines are able to spread from the primary lesion and take up residence in distant sites. If the primary tumors were resected at 3 weeks, in several cases, metastastic lesions were identified over the course of 9 months. We propose that this new model may be particularly useful in exploring the molecular events in early metastasis, identifying the metastatic niche, and studying issues pertaining to dormancy.

  7. Resveratrol Neuroprotection in a Chronic Mouse Model of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Zoe eFonseca-Kelly

    2012-05-01

    Full Text Available Resveratrol is a naturally-occurring polyphenol that activates SIRT1, an NAD-dependent deacetylase. SRT501, a pharmaceutical formulation of resveratrol with enhanced systemic absorption, prevents neuronal loss without suppressing inflammation in mice with relapsing experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis. In contrast, resveratrol has been reported to suppress inflammation in chronic EAE, although neuroprotective effects were not evaluated. The current studies examine potential neuroprotective and immunomodulatory effects of resveratrol in chronic EAE induced by immunization with myelin oligodendroglial glycoprotein peptide in C57/Bl6 mice. Effects of two distinct formulations of resveratrol administered daily orally were compared. Resveratrol delayed the onset of EAE compared to vehicle-treated EAE mice, but did not prevent or alter the phenotype of inflammation in spinal cords or optic nerves. Significant neuroprotective effects were observed, with higher numbers of retinal ganglion cells found in eyes of resveratrol-treated EAE mice with optic nerve inflammation. Results demonstrate that resveratrol prevents neuronal loss in this chronic demyelinating disease model, similar to its effects in relapsing EAE. Differences in immunosuppression compared with prior studies suggest that immunomodulatory effects may be limited and may depend on specific immunization parameters or timing of treatment. Importantly, neuroprotective effects can occur without immunosuppression, suggesting a potential additive benefit of resveratrol in combination with anti-inflammatory therapies for multiple sclerosis.

  8. Mouse models for the study of postnatal cardiac hypertrophy

    Directory of Open Access Journals (Sweden)

    A. Del Olmo-Turrubiarte

    2015-06-01

    Full Text Available The main objective of this study was to create a postnatal model for cardiac hypertrophy (CH, in order to explain the mechanisms that are present in childhood cardiac hypertrophy. Five days after implantation, intraperitoneal (IP isoproterenol (ISO was injected for 7 days to pregnant female mice. The fetuses were obtained at 15, 17 and 19 dpc from both groups, also newborns (NB, neonates (7–15 days and young adults (6 weeks of age. Histopathological exams were done on the hearts. Immunohistochemistry and western blot demonstrated GATA4 and PCNA protein expression, qPCR real time the mRNA of adrenergic receptors (α-AR and β-AR, alpha and beta myosins (α-MHC, β-MHC and GATA4. After the administration of ISO, there was no change in the number of offsprings. We observed significant structural changes in the size of the offspring hearts. Morphometric analysis revealed an increase in the size of the left ventricular wall and interventricular septum (IVS. Histopathological analysis demonstrated loss of cellular compaction and presence of left ventricular small fibrous foci after birth. Adrenergic receptors might be responsible for changing a physiological into a pathological hypertrophy. However GATA4 seemed to be the determining factor in the pathology. A new animal model was established for the study of pathologic CH in early postnatal stages.

  9. Insights into the immunopathogenesis of malaria using mouse models.

    Science.gov (United States)

    Lamb, Tracey J; Brown, Douglas E; Potocnik, Alexandre J; Langhorne, Jean

    2006-03-23

    Malaria kills approximately 1-2 million people every year, mostly in sub-Saharan Africa and in Asia. These deaths are at the most severe end of a scale of pathologies affecting approximately 500 million people per year. Much of the pathogenesis of malaria is caused by inappropriate or excessive immune responses mounted by the body to eliminate malaria parasites. In this review, we examine the evidence that immunopathology is responsible for malaria disease in the context of what we have learnt from animal models of malaria. In particular, we look in detail at the processes involved in endothelial cell damage leading to syndromes such as cerebral malaria, as well as generalised systemic manifestations such as anaemia, cachexia and problems with thermoregulation of the body. We also consider malaria in light of the variation of the severity of disease observed among people, and discuss the contribution from animal models to our understanding of this variation. Finally, we discuss some of the implications of immunopathology, and of host and parasite genetic variation, for the design and implementation of anti-malarial vaccines.

  10. Transgenic Mouse Model for Reducing Oxidative Damage in Bone

    Science.gov (United States)

    Schreurs, Ann-Sofie; Torres, S.; Truong, T.; Moyer, E. L.; Kumar, A.; Tahimic, Candice C. G.; Alwood, J. S.; Limoli, C. L.; Globus, R. K.

    2016-01-01

    Bone loss can occur due to many challenges such age, radiation, microgravity, and Reactive Oxygen Species (ROS) play a critical role in bone resorption by osteoclasts (Bartell et al. 2014). We hypothesize that suppression of excess ROS in skeletal cells, both osteoblasts and osteoclasts, regulates skeletal growth and remodeling. To test our hypothesis, we used transgenic mCAT mice which overexpress the human anti-oxidant catalase gene targeted to the mitochondria, the main site for endogenous ROS production. mCAT mice have a longer life-span than wildtype controls and have been used to study various age-related disorders. To stimulate remodeling, 16 week old mCAT mice or wildtype mice were exposed to treatment (hindlimb-unloading and total body-irradiation) or sham treatment conditions (control). Tissues were harvested 2 weeks later for skeletal analysis (microcomputed tomography), biochemical analysis (gene expression and oxidative damage measurements), and ex vivo bone marrow derived cell culture (osteoblastogenesis and osteoclastogenesis). mCAT mice expressed the transgene and displayed elevated catalase activity in skeletal tissue and marrow-derived osteoblasts and osteoclasts grown ex vivo. In addition, when challenged with treatment, bone tissues from wildtype mice showed elevated levels of malondialdehyde (MDA), indicating oxidative damage) whereas mCAT mice did not. Correlation analysis revealed that increased catalase activity significantly correlated with decreased MDA levels and that increased oxidative damage correlated with decreased percent bone volume (BVTV). In addition, ex-vivo cultured osteoblast colony growth correlated with catalase activity in the osteoblasts. Thus, we showed that these transgenic mice can be used as a model to study the relationship between markers of oxidative damage and skeletal properties. mCAT mice displayed reduced BVTV and trabecular number relative to wildtype mice, as well as increased structural model index in the

  11. Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma

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    Lawrence N. Kwong

    2017-05-01

    Full Text Available Tumor evolution is an iterative process of selection for pro-oncogenic aberrations. This process can be accelerated by genomic instability, but how it interacts with different selection bottlenecks to shape the evolving genomic landscape remains understudied. Here, we assessed tumor initiation and therapy resistance bottlenecks in mouse models of melanoma, with or without genomic instability. At the initiation bottleneck, whole-exome sequencing revealed that drug-naive tumors were genomically silent, and this was surprisingly unaffected when genomic instability was introduced via telomerase inactivation. We hypothesize that the strong engineered alleles created low selection pressure. At the therapy resistance bottleneck, strong selective pressure was applied using a BRAF inhibitor. In the absence of genomic instability, tumors acquired a non-genomic drug resistance mechanism. By contrast, telomerase-deficient, drug-resistant melanomas acquired highly recurrent copy number gains. These proof-of-principle experiments demonstrate how different selection pressures can interact with genomic instability to impact tumor evolution.

  12. Development of a Mouse Model of Abdominal Cutaneous Flaps for Breast Reconstruction

    OpenAIRE

    Daniel John Womac; Arun Prathap Palanisamy; Rene Eslick; Dennis Kenneth Schimpf; Kenneth David Chavin

    2013-01-01

    UNLABELLED: Autologous tissue transfer, in addition to replacing tissue that was lost during injury or surgery, offers women an excellent option to improve cosmetic appearance and self-confidence following mastectomy due to breast cancer. However, flap necrosis is a complication in obese patients undergoing this procedure. We created a mouse model to study the flap-related complications that leads to decreased flap survival in autologous breast reconstruction. METHODS: Left superficial inferi...

  13. Mouse model of diffuse brain damage following anoxia, evaluated by a new assay of generalized arousal

    OpenAIRE

    Arrieta-Cruz, Isabel; Pfaff, Donald W.; Shelley, Deborah N.

    2007-01-01

    Diffuse brain damage following anoxia due to cardiac failure, drowning, carbon monoxide exposure or other accidents constitutes a major medical problem. We have created a novel mouse model using the breathing of pure nitrogen, followed by a recently developed assay that reflects an operational definition of generalized arousal. The operational definition is precise, complete, and leads to quantitative, physical measures in a genetically tractable animal. Exposure to pure nitrogen for controll...

  14. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

    OpenAIRE

    Irukayama-Tomobe, Yoko; Ogawa, Yasuhiro; Tominaga, Hiromu; Ishikawa, Yukiko; Hosokawa, Naoto; Ambai, Shinobu; Kawabe, Yuki; Uchida, Shuntaro; Nakajima, Ryo; Saitoh, Tsuyoshi; Kanda, Takeshi; Vogt, Kaspar; Sakurai, Takeshi; Nagase, Hiroshi; Yanagisawa, Masashi

    2017-01-01

    Narcolepsy-cataplexy is a debilitating disorder characterized by excessive daytime sleepiness (sleep attacks) and cataplexy, a sudden bilateral loss of muscle tone often triggered by emotion. The disease is caused by a selective loss of hypothalamic neurons producing the neuropeptide orexin. Currently, only symptomatic therapies are available for narcolepsy. Here, we examine the pharmacological effect of YNT-185, a nonpeptide, selective agonist for the orexin type-2 receptor in mouse models o...

  15. Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

    OpenAIRE

    Rooney, Jachinta E.; Gurpur, Praveen B.; Burkin, Dean J.

    2009-01-01

    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α7β1-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α7-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological ...

  16. Obesity-Linked Mouse Models of Liver Cancer | Center for Cancer Research

    Science.gov (United States)

    Jimmy Stauffer, Ph.D., and colleagues working with Robert  Wiltrout, Ph.D., in CCR’s Cancer and Inflammation Program, along with collaborators in the Laboratory of Human Carcinogenesis, have developed a novel mouse model that demonstrates how fat-producing phenotypes can influence the development of hepatic cancer.   The team recently reported their findings in Cancer Research.

  17. A Mouse Model to Investigate Postmenopausal Biology as an Etiology of Ovarian Cancer

    Science.gov (United States)

    2008-11-01

    mice will be injected into the ovarian bursa with Adv-cre to delete p53 and Adv-lacZ as controls in the ovarian surface epithelial cells. Currently...injection into ovarian bursa has been well established, and Adv-cre injection has been successfully used in several mouse models of ovarian tumors...surface and the bursa inner layer of cells (Figure 5). We conclude that adenoviral delivery of cre into ovarian bursa is efficient and technically

  18. Noninvasive Imaging of Natural Killer Cell-Mediated Apoptosis in a Mouse Tumor Model.

    Science.gov (United States)

    Singh, Thoudam Debraj; Lee, Jaetae; Jeon, Yong Hyun

    2016-01-01

    Natural killer (NK) cells are cytotoxic lymphocytes that induce apoptosis in cancer cells infected with viruses and bacteria through a caspase-3-dependent pathway. Effective NK cell-based immunotherapy requires highly sensitive imaging tools for in vivo monitoring of the dynamic events involved in apoptosis. Here, we describe a noninvasive bioluminescence imaging approach to determine the antitumor effects of NK cell-based therapy by serial imaging of caspase-3-dependent apoptosis in a mouse model of human glioma.

  19. Metformin blocks progression of obesity-activated thyroid cancer in a mouse model

    OpenAIRE

    Park, Jeongwon; Kim, Won Gu; Zhao, Li; Enomoto, Keisuke; Willingham, Mark; Cheng, Sheue-yann

    2016-01-01

    Compelling epidemiologic evidence indicates that obesity is associated with a high risk of human malignancies, including thyroid cancer. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (ThrbPV/PVPten +/?mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other ...

  20. Usefulness of running wheel for detection of congestive heart failure in dilated cardiomyopathy mouse model.

    Science.gov (United States)

    Sugihara, Masami; Odagiri, Fuminori; Suzuki, Takeshi; Murayama, Takashi; Nakazato, Yuji; Unuma, Kana; Yoshida, Ken-ichi; Daida, Hiroyuki; Sakurai, Takashi; Morimoto, Sachio; Kurebayashi, Nagomi

    2013-01-01

    Inherited dilated cardiomyopathy (DCM) is a progressive disease that often results in death from congestive heart failure (CHF) or sudden cardiac death (SCD). Mouse models with human DCM mutation are useful to investigate the developmental mechanisms of CHF and SCD, but knowledge of the severity of CHF in live mice is necessary. We aimed to diagnose CHF in live DCM model mice by measuring voluntary exercise using a running wheel and to determine causes of death in these mice. A knock-in mouse with a mutation in cardiac troponin T (ΔK210) (DCM mouse), which results in frequent death with a t(1/2) of 70 to 90 days, was used as a DCM model. Until 2 months of age, average wheel-running activity was similar between wild-type and DCM mice (approximately 7 km/day). At approximately 3 months, some DCM mice demonstrated low running activity (LO: 5 km/day). In the LO group, the lung weight/body weight ratio was much higher than that in the other groups, and the lungs were infiltrated with hemosiderin-loaded alveolar macrophages. Furthermore, echocardiography showed more severe ventricular dilation and a lower ejection fraction, whereas Electrocardiography (ECG) revealed QRS widening. There were two patterns in the time courses of running activity before death in DCM mice: deaths with maintained activity and deaths with decreased activity. Our results indicate that DCM mice with low running activity developed severe CHF and that running wheels are useful for detection of CHF in mouse models. We found that approximately half of ΔK210 DCM mice die suddenly before onset of CHF, whereas others develop CHF, deteriorate within 10 to 20 days, and die.

  1. Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models

    OpenAIRE

    Vuguin, P. M.; Charron, M J

    2011-01-01

    Using knockout and transgenic technology, genetically modified animal models allowed us to understand the role of glucagon signalling in metabolism. Mice with a global deletion of the glucagon receptor gene (Gcgr) were designed using gene targeting. The phenotype of Gcgr−/− mouse provided important clues about the role of Gcgr in foetal growth, pancreatic development and glucose and lipid homeostasis. The lack of Gcgr activation was associated with: (i) hypoglycaemic pregnancies, poor foetal ...

  2. Vanadium Inhalation in a Mouse Model for the Understanding of Air-Suspended Particle Systemic Repercussion

    Directory of Open Access Journals (Sweden)

    T. I. Fortoul

    2011-01-01

    Full Text Available There is an increased concern about the health effects that air-suspended particles have on human health which have been dissected in animal models. Using CD-1 mouse, we explore the effects that vanadium inhalation produce in different tissues and organs. Our findings support the systemic effects of air pollution. In this paper, we describe our findings in different organs in our conditions and contrast our results with the literature.

  3. Usefulness of running wheel for detection of congestive heart failure in dilated cardiomyopathy mouse model.

    Directory of Open Access Journals (Sweden)

    Masami Sugihara

    Full Text Available BACKGROUND: Inherited dilated cardiomyopathy (DCM is a progressive disease that often results in death from congestive heart failure (CHF or sudden cardiac death (SCD. Mouse models with human DCM mutation are useful to investigate the developmental mechanisms of CHF and SCD, but knowledge of the severity of CHF in live mice is necessary. We aimed to diagnose CHF in live DCM model mice by measuring voluntary exercise using a running wheel and to determine causes of death in these mice. METHODOLOGY/PRINCIPAL FINDINGS: A knock-in mouse with a mutation in cardiac troponin T (ΔK210 (DCM mouse, which results in frequent death with a t(1/2 of 70 to 90 days, was used as a DCM model. Until 2 months of age, average wheel-running activity was similar between wild-type and DCM mice (approximately 7 km/day. At approximately 3 months, some DCM mice demonstrated low running activity (LO: 5 km/day. In the LO group, the lung weight/body weight ratio was much higher than that in the other groups, and the lungs were infiltrated with hemosiderin-loaded alveolar macrophages. Furthermore, echocardiography showed more severe ventricular dilation and a lower ejection fraction, whereas Electrocardiography (ECG revealed QRS widening. There were two patterns in the time courses of running activity before death in DCM mice: deaths with maintained activity and deaths with decreased activity. CONCLUSIONS/SIGNIFICANCE: Our results indicate that DCM mice with low running activity developed severe CHF and that running wheels are useful for detection of CHF in mouse models. We found that approximately half of ΔK210 DCM mice die suddenly before onset of CHF, whereas others develop CHF, deteriorate within 10 to 20 days, and die.

  4. Calea zacatechichi dichloromethane extract exhibits antidiarrheal and antinociceptive effects in mouse models mimicking irritable bowel syndrome

    OpenAIRE

    Sałaga, M.; Kowalczuk, A.; Zielinska, M.; Błażewicz, A.; Fichna, J.

    2015-01-01

    Calea zacatechichi Schltdl. (Asteraceae alt. Compositae) is a Mexican plant commonly used in folk medicine to treat respiratory and gastrointestinal (GI) disorders. The objective of this study is to characterize the effect of C. zacatechichi extracts in mouse models mimicking the symptoms of irritable bowel syndrome (IBS). Powdered C. zacatechichi herb (leaves, stems, and flowers) was extracted with methanol. Methanolic extract was filtered and evaporated giving methanolic fraction. The resid...

  5. Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters†

    OpenAIRE

    Maeda, Akiko; Maeda, Tadao; Imanishi, Yoshikazu; Golczak, Marcin; Moise, Alexander R.; Palczewski, Krzysztof

    2006-01-01

    Regeneration of the visual chromophore, 11-cis-retinal, is a critical step in restoring photoreceptors to their dark-adapted conditions. This regeneration process, called the retinoid cycle, takes place in the photoreceptor outer segments and the retinal pigment epithelium (RPE). Disabling mutations in nearly all of the retinoid cycle genes are linked to human conditions that cause congenital or progressive defects in vision. Several mouse models with disrupted genes related to this cycle con...

  6. Glyburide reduces bacterial dissemination in a mouse model of melioidosis.

    Science.gov (United States)

    Koh, Gavin C K W; Weehuizen, Tassili A; Breitbach, Katrin; Krause, Kathrin; de Jong, Hanna K; Kager, Liesbeth M; Hoogendijk, Arjan J; Bast, Antje; Peacock, Sharon J; van der Poll, Tom; Steinmetz, Ivo; Wiersinga, W Joost

    2013-01-01

    Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ~40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide ( = glibenclamide) prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis. Mice (C57BL/6) with streptozocin-induced diabetes were inoculated with ~6 × 10(2) cfu B. pseudomallei intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after inoculation) in order to mimic the clinical scenario. Glyburide (50 mg/kg) or vehicle was started 7 d before inoculation and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by broth microdilution. We also examined the effect of glyburide on interleukin (IL) 1β by bone-marrow-derived macrophages (BMDM). Diabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and reduced IL1β production when compared to untreated controls. Other cytokines were not different in glyburide-treated animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the secretion of IL1β by BMDMs in a dose-dependent fashion. Diabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1β secretion accompanied by diminished cellular

  7. Systematic construction of a conceptual minimal model of plasma cholesterol levels based on knockout mouse phenotypes.

    Science.gov (United States)

    van de Pas, Niek C A; Soffers, Ans E M F; Freidig, Andreas P; van Ommen, Ben; Woutersen, Ruud A; Rietjens, Ivonne M C M; de Graaf, Albert A

    2010-06-01

    Elevated plasma cholesterol, a well-known risk factor for cardiovascular diseases, is the result of the activity of many genes and their encoded proteins in a complex physiological network. We aim to develop a minimal kinetic computational model for predicting plasma cholesterol levels. To define the scope of this model, it is essential to discriminate between important and less important processes influencing plasma cholesterol levels. To this end, we performed a systematic review of mouse knockout strains and used the resulting dataset, named KOMDIP, for the identification of key genes that determine plasma cholesterol levels. Based on the described phenotype of mouse knockout models, 36 of the 120 evaluated genes were marked as key genes that have a pronounced effect on the plasma cholesterol concentration. The key genes include well-known genes, e.g., Apoe and Ldlr, as well as genes hardly linked to cholesterol metabolism so far, e.g., Plagl2 and Slc37a4. Based on the catalytic function of the genes, a minimal conceptual model was defined. A comparison with nine conceptual models from literature revealed that each of the individual published models is less complete than our model. Concluding, we have developed a conceptual model that can be used to develop a physiologically based kinetic model to quantitatively predict plasma cholesterol levels. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  8. The PPCD1 mouse: characterization of a mouse model for posterior polymorphous corneal dystrophy and identification of a candidate gene.

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    Anna L Shen

    2010-08-01

    Full Text Available The PPCD1 mouse, a spontaneous mutant that arose in our mouse colony, is characterized by an enlarged anterior chamber resulting from metaplasia of the corneal endothelium and blockage of the iridocorneal angle by epithelialized corneal endothelial cells. The presence of stratified multilayered corneal endothelial cells with abnormal patterns of cytokeratin expression are remarkably similar to those observed in human posterior polymorphous corneal dystrophy (PPCD and the sporadic condition, iridocorneal endothelial syndrome. Affected eyes exhibit epithelialized corneal endothelial cells, with inappropriate cytokeratin expression and proliferation over the iridocorneal angle and posterior cornea. We have termed this the "mouse PPCD1" phenotype and mapped the mouse locus for this phenotype, designated "Ppcd1", to a 6.1 Mbp interval on Chromosome 2, which is syntenic to the human Chromosome 20 PPCD1 interval. Inheritance of the mouse PPCD1 phenotype is autosomal dominant, with complete penetrance on the sensitive DBA/2J background and decreased penetrance on the C57BL/6J background. Comparative genome hybridization has identified a hemizygous 78 Kbp duplication in the mapped interval. The endpoints of the duplication are located in positions that disrupt the genes Csrp2bp and 6330439K17Rik and lead to duplication of the pseudogene LOC100043552. Quantitative reverse transcriptase-PCR indicates that expression levels of Csrp2bp and 6330439K17Rik are decreased in eyes of PPCD1 mice. Based on the observations of decreased gene expression levels, association with ZEB1-related pathways, and the report of corneal opacities in Csrp2bp(tm1a(KOMPWtsi heterozygotes and embryonic lethality in nulls, we postulate that duplication of the 78 Kbp segment leading to haploinsufficiency of Csrp2bp is responsible for the mouse PPCD1 phenotype. Similarly, CSRP2BP haploinsufficiency may lead to human PPCD.

  9. Inflammatory Cytokine Pattern Is Sex-Dependent in Mouse Cutaneous Melanoma Experimental Model

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    Mihaela Surcel

    2017-01-01

    Full Text Available We present the evaluation of inflammatory cytokines in mouse cutaneous melanoma experimental model, as markers of disease evolution. Moreover, to test our experimental model, we have used low doses of dacarbazine (DTIC. C57 BL/6J mouse of both sexes were subjected to experimental cutaneous melanoma and treated with low doses of DTIC. Clinical parameters and serum cytokines were followed during tumor evolution and during DTIC therapy. Cytokine/chemokine pattern was assessed using xMAP technology and the following molecules were quantified: interleukins (IL-1-beta, IL-6, IL-10, IL-12 (p70, interferon (IFN-gamma, granulocyte macrophage colony-stimulating factor (GM-CSF, tumor necrosis factor (TNF-alpha, macrophage inflammatory protein (MIP-1alpha, monocyte chemoattractant protein (MCP-1, and keratinocyte-derived chemokine (KC. Significant differences were found between normal females and males mice, female mice having a statistically higher serum concentration of IL-1-beta compared to male mice, while males have a significantly higher concentration of MIP-1-alpha. During melanoma evolution in the female group, IL-1-beta, MIP-1-alpha, and KC circulatory levels were found 10-fold increased, while other cytokines doubled their values. In the male mice group, only circulatory KC increased 4 times, while IL-1-beta and TNF-alpha doubled their circulatory values. Various serum cytokines correlated with the disease evolution in cutaneous melanoma mouse model.

  10. Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy.

    Science.gov (United States)

    Zimova, Ivana; Brezovakova, Veronika; Hromadka, Tomas; Weisova, Petronela; Cubinkova, Veronika; Valachova, Bernadeta; Filipcik, Peter; Jadhav, Santosh; Smolek, Tomas; Novak, Michal; Zilka, Norbert

    2016-09-06

    Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

  11. Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease.

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    Géraldine H Petit

    Full Text Available Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.

  12. Obesity increases tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer.

    Science.gov (United States)

    Makowski, Liza; Zhou, Chunxiao; Zhong, Yan; Kuan, Pei Fen; Fan, Cheng; Sampey, Brante P; Difurio, Megan; Bae-Jump, Victoria L

    2014-04-01

    Obesity is associated with increased risk and worse outcomes for ovarian cancer. Thus, we examined the effects of obesity on ovarian cancer progression in a genetically engineered mouse model of serous ovarian cancer. We utilized a unique serous ovarian cancer mouse model that specifically deletes the tumor suppressor genes, Brca1 and p53, and inactivates the retinoblastoma (Rb) proteins in adult ovarian surface epithelial cells, via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice (KpB mouse model). KpB mice were subjected to a 60% calories-derived from fat in a high fat diet (HFD) versus 10% calories from fat in a low fat diet (LFD) to mimic diet-induced obesity. Tumors were isolated at 6 months after AdCre injection and evaluated histologically. Untargeted metabolomic and gene expression profiling was performed to assess differences in the ovarian tumors from obese versus non-obese KpB mice. At sacrifice, mice on the HFD (obese) were twice the weight of mice on the LFD (non-obese) (51g versus 31g, p=0.0003). Ovarian tumors were significantly larger in the obese versus non-obese mice (3.7cm(2) versus 1.2cm(2), p=0.0065). Gene expression and metabolomic profiling indicated statistically significant differences between the ovarian tumors from the obese versus non-obese mice, including metabolically relevant pathways. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Biology and therapy of inherited retinal degenerative disease: insights from mouse models

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    Shobi Veleri

    2015-02-01

    Full Text Available Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.

  14. Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model

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    Jinu Abraham

    2011-01-01

    Full Text Available Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR has been found to be expressed and activated in human rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for alveolar rhabdomyosarcoma (ARMS which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of alveolar rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of alveolar rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in alveolar rhabdomyosarcoma.

  15. Longitudinal in vivo muscle function analysis of the DMSXL mouse model of myotonic dystrophy type 1.

    Science.gov (United States)

    Decostre, Valérie; Vignaud, Alban; Matot, Béatrice; Huguet, Aline; Ledoux, Isabelle; Bertil, Emilie; Gjata, Bernard; Carlier, Pierre G; Gourdon, Geneviève; Hogrel, Jean-Yves

    2013-12-01

    Myotonic dystrophy is the most common adult muscle dystrophy. In view of emerging therapies, which use animal models as a proof of principle, the development of reliable outcome measures for in vivo longitudinal study of mouse skeletal muscle function is becoming crucial. To satisfy this need, we have developed a device to measure ankle dorsi- and plantarflexion torque in rodents. We present an in vivo 8-month longitudinal study of the contractile properties of the skeletal muscles of the DMSXL mouse model of myotonic dystrophy type 1. Between 4 and 12 months of age, we observed a reduction in muscle strength in the ankle dorsi- and plantarflexors of DMSXL compared to control mice although the strength per muscle cross-section was normal. Mild steady myotonia but no abnormal muscle fatigue was also observed in the DMSXL mice. Magnetic resonance imaging and histological analysis performed at the end of the study showed respectively reduced muscle cross-section area and smaller muscle fibre diameter in DMSXL mice. In conclusion, our study demonstrates the feasibility of carrying out longitudinal in vivo studies of muscle function over several months in a mouse model of myotonic dystrophy confirming the feasibility of this method to test preclinical therapeutics. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Mouse Models of Down Syndrome as a Tool to Unravel the Causes of Mental Disabilities

    Science.gov (United States)

    Rueda, Noemí; Flórez, Jesús; Martínez-Cué, Carmen

    2012-01-01

    Down syndrome (DS) is the most common genetic cause of mental disability. Based on the homology of Hsa21 and the murine chromosomes Mmu16, Mmu17 and Mmu10, several mouse models of DS have been developed. The most commonly used model, the Ts65Dn mouse, has been widely used to investigate the neural mechanisms underlying the mental disabilities seen in DS individuals. A wide array of neuromorphological alterations appears to compromise cognitive performance in trisomic mice. Enhanced inhibition due to alterations in GABAA-mediated transmission and disturbances in the glutamatergic, noradrenergic and cholinergic systems, among others, has also been demonstrated. DS cognitive dysfunction caused by neurodevelopmental alterations is worsened in later life stages by neurodegenerative processes. A number of pharmacological therapies have been shown to partially restore morphological anomalies concomitantly with cognition in these mice. In conclusion, the use of mouse models is enormously effective in the study of the neurobiological substrates of mental disabilities in DS and in the testing of therapies that rescue these alterations. These studies provide the basis for developing clinical trials in DS individuals and sustain the hope that some of these drugs will be useful in rescuing mental disabilities in DS individuals. PMID:22685678

  17. Glyburide reduces bacterial dissemination in a mouse model of melioidosis.

    Directory of Open Access Journals (Sweden)

    Gavin C K W Koh

    Full Text Available Burkholderia pseudomallei infection (melioidosis is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ~40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide ( = glibenclamide prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis.Mice (C57BL/6 with streptozocin-induced diabetes were inoculated with ~6 × 10(2 cfu B. pseudomallei intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after inoculation in order to mimic the clinical scenario. Glyburide (50 mg/kg or vehicle was started 7 d before inoculation and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by broth microdilution. We also examined the effect of glyburide on interleukin (IL 1β by bone-marrow-derived macrophages (BMDM.Diabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and reduced IL1β production when compared to untreated controls. Other cytokines were not different in glyburide-treated animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the secretion of IL1β by BMDMs in a dose-dependent fashion.Diabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1β secretion accompanied by diminished

  18. Epithelial morphogenesis: the mouse eye as a model system.

    Science.gov (United States)

    Chauhan, Bharesh; Plageman, Timothy; Lou, Ming; Lang, Richard

    2015-01-01

    Morphogenesis is the developmental process by which tissues and organs acquire the shape that is critical to their function. Here, we review recent advances in our understanding of the mechanisms that drive morphogenesis in the developing eye. These investigations have shown that regulation of the actin cytoskeleton is central to shaping the presumptive lens and retinal epithelia that are the major components of the eye. Regulation of the actin cytoskeleton is mediated by Rho family GTPases, by signaling pathways and indirectly, by transcription factors that govern the expression of critical genes. Changes in the actin cytoskeleton can shape cells through the generation of filopodia (that, in the eye, connect adjacent epithelia) or through apical constriction, a process that produces a wedge-shaped cell. We have also learned that one tissue can influence the shape of an adjacent one, probably by direct force transmission, in a process we term inductive morphogenesis. Though these mechanisms of morphogenesis have been identified using the eye as a model system, they are likely to apply broadly where epithelia influence the shape of organs during development. © 2015 Elsevier Inc. All rights reserved.

  19. Altered Erythropoiesis in Mouse Models of Type 3 Hemochromatosis

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    R. M. Pellegrino

    2017-01-01

    Full Text Available Type 3 haemochromatosis (HFE3 is a rare genetic iron overload disease which ultimately lead to compromised organs functioning. HFE3 is caused by mutations in transferrin receptor 2 (TFR2 gene that codes for two main isoforms (Tfr2α and Tfr2β. Tfr2α is one of the hepatic regulators of iron inhibitor hepcidin. Tfr2β is an intracellular isoform of the protein involved in the regulation of iron levels in reticuloendothelial cells. It has been recently demonstrated that Tfr2 is also involved in erythropoiesis. This study aims to further investigate Tfr2 erythropoietic role by evaluating the erythropoiesis of two Tfr2 murine models wherein either one or both of Tfr2 isoforms have been selectively silenced (Tfr2 KI and Tfr2 KO. The evaluations were performed in bone marrow and spleen, in 14 days’ and 10 weeks’ old mice, to assess erythropoiesis in young versus adult animals. The lack of Tfr2α leads to macrocytosis with low reticulocyte number and increased hemoglobin values, together with an anticipation of adult BM erythropoiesis and an increased splenic erythropoiesis. On the other hand, lack of Tfr2β (Tfr2 KI mice causes an increased and immature splenic erythropoiesis. Taken together, these data confirm the role of Tfr2α in modulation of erythropoiesis and of Tfr2β in favoring iron availability for erythropoiesis.

  20. Altered Erythropoiesis in Mouse Models of Type 3 Hemochromatosis.

    Science.gov (United States)

    Pellegrino, R M; Riondato, F; Ferbo, L; Boero, M; Palmieri, A; Osella, L; Pollicino, P; Miniscalco, B; Saglio, G; Roetto, A

    2017-01-01

    Type 3 haemochromatosis (HFE3) is a rare genetic iron overload disease which ultimately lead to compromised organs functioning. HFE3 is caused by mutations in transferrin receptor 2 (TFR2) gene that codes for two main isoforms (Tfr2α and Tfr2β). Tfr2α is one of the hepatic regulators of iron inhibitor hepcidin. Tfr2β is an intracellular isoform of the protein involved in the regulation of iron levels in reticuloendothelial cells. It has been recently demonstrated that Tfr2 is also involved in erythropoiesis. This study aims to further investigate Tfr2 erythropoietic role by evaluating the erythropoiesis of two Tfr2 murine models wherein either one or both of Tfr2 isoforms have been selectively silenced (Tfr2 KI and Tfr2 KO). The evaluations were performed in bone marrow and spleen, in 14 days' and 10 weeks' old mice, to assess erythropoiesis in young versus adult animals. The lack of Tfr2α leads to macrocytosis with low reticulocyte number and increased hemoglobin values, together with an anticipation of adult BM erythropoiesis and an increased splenic erythropoiesis. On the other hand, lack of Tfr2β (Tfr2 KI mice) causes an increased and immature splenic erythropoiesis. Taken together, these data confirm the role of Tfr2α in modulation of erythropoiesis and of Tfr2β in favoring iron availability for erythropoiesis.

  1. Proteomic Characterization of a Mouse Model of Familial Danish Dementia

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    Monica Vitale

    2012-01-01

    Full Text Available A dominant mutation in the ITM2B/BRI2 gene causes familial Danish dementia (FDD in humans. To model FDD in animal systems, a knock-in approach was recently implemented in mice expressing a wild-type and mutant allele, which bears the FDD-associated mutation. Since these FDDKI mice show behavioural alterations and impaired synaptic function, we characterized their synaptosomal proteome via two-dimensional differential in-gel electrophoresis. After identification by nanoliquid chromatography coupled to electrospray-linear ion trap tandem mass spectrometry, the differentially expressed proteins were classified according to their gene ontology descriptions and their predicted functional interactions. The Dlg4/Psd95 scaffold protein and additional signalling proteins, including protein phosphatases, were revealed by STRING analysis as potential players in the altered synaptic function of FDDKI mice. Immunoblotting analysis finally demonstrated the actual downregulation of the synaptosomal scaffold protein Dlg4/Psd95 and of the dual-specificity phosphatase Dusp3 in the synaptosomes of FDDKI mice.

  2. Therapeutic liver repopulation in a mouse model of hypercholesterolemia.

    Science.gov (United States)

    Mitchell, C; Mignon, A; Guidotti, J E; Besnard, S; Fabre, M; Duverger, N; Parlier, D; Tedgui, A; Kahn, A; Gilgenkrantz, H

    2000-07-01

    Liver repopulation constitutes an attractive approach for the treatment of liver disorders or of diseases requiring abundant secretion of an active protein. We have described previously a model of selective repopulation of a normal liver by Fas/CD95-resistant hepatocytes, in which we achieved up to 16% hepatocyte repopulation. In the present study, we investigated the therapeutic efficacy of this strategy. With this aim, apolipoprotein E (ApoE) knockout mice were transplanted with Fas/CD95-resistant hepatocytes which constitutively express ApoE. Transplanted mice were submitted to weekly injections of non-lethal doses of the Fas agonist antibody Jo2. After 8 weeks of treatment, we obtained up to 30% of the normal level of plasma ApoE. ApoE secretion was accompanied by a drastic and significant decrease in total plasma cholesterol, which even fell to normal levels. Moreover, this secretion was sufficient to markedly reduce the progression of atherosclerosis. These results demonstrate the efficacy of this repopulation approach for correcting a deficiency in a protein secreted by the liver.

  3. A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells

    OpenAIRE

    Shamsi, Farnaz; Parlato, Rosanna; Collombat, Patrick; Mansouri, Ahmed

    2014-01-01

    The putative induction of adult β-cell regeneration represents a promising approach for the treatment of type 1 diabetes. Toward this ultimate goal, it is essential to develop an inducible model mimicking the long-lasting disease progression. In the current study, we have established a novel β-cell ablation mouse model, in which the β-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the β-cell specific genetic ablation of the transcription initiation factor ...

  4. Behavioral and neurochemical characterization of new mouse model of hyperphenylalaninemia.

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    Tiziana Pascucci

    Full Text Available Hyperphenylalaninemia (HPA refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU (PHE > 1200 µM/L, mild PKU (PHE 600-1200 µM/L and persistent HPA (PHE 120-600 µM/L (normal blood PHE < 120 µM/L. The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU, developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE.

  5. Behavioral and Neurochemical Characterization of New Mouse Model of Hyperphenylalaninemia

    Science.gov (United States)

    Pascucci, Tiziana; Giacovazzo, Giacomo; Andolina, Diego; Accoto, Alessandra; Fiori, Elena; Ventura, Rossella; Orsini, Cristina; Conversi, David; Carducci, Claudia; Leuzzi, Vincenzo; Puglisi-Allegra, Stefano

    2013-01-01

    Hyperphenylalaninemia (HPA) refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE) in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU) (PHE > 1200 µM/L), mild PKU (PHE 600-1200 µM/L) and persistent HPA (PHE 120-600 µM/L) (normal blood PHE < 120 µM/L). The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU), developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE. PMID:24376837

  6. Enhanced operant extinction and prefrontal excitability in a mouse model of Angelman syndrome.

    Science.gov (United States)

    Sidorov, Michael S; Judson, Matthew C; Kim, Hyojin; Rougie, Marie; Ferrer, Alejandra I; Nikolova, Viktoriya D; Riddick, Natallia V; Moy, Sheryl S; Philpot, Benjamin D

    2018-02-05

    Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of UBE3A in neurons. Mouse models of AS faithfully recapitulate disease phenotypes across multiple domains, including behavior. Yet in AS, there has been only limited study of behaviors encoded by the prefrontal cortex, a region broadly involved in executive function and cognition. Because cognitive impairment is a core feature of AS, it is critical to develop behavioral readouts of prefrontal circuit function in AS mouse models. One such readout is behavioral extinction, which has been well-described mechanistically and relies upon prefrontal circuits in rodents. Here we report exaggerated operant extinction in male AS model mice, concomitant with enhanced excitability in medial prefrontal neurons from male and female AS model mice. Abnormal behavior was specific to operant extinction, as two other prefrontally-dependent tasks (cued fear extinction and visuospatial discrimination) were largely normal in AS model mice. Inducible deletion of Ube3a during adulthood was not sufficient to drive abnormal extinction, supporting the hypothesis that there is an early critical period for development of cognitive phenotypes in AS. This work represents the first formal experimental analysis of prefrontal circuit function in AS, and identifies operant extinction as a useful experimental paradigm for modeling cognitive aspects of AS in mice. SIGNIFICANCE STATEMENT Prefrontal cortex encodes "high-level" cognitive processes. Thus, understanding prefrontal function is critical in neurodevelopmental disorders where cognitive impairment is highly penetrant. Angelman syndrome is a neurodevelopmental disorder associated with speech and motor impairments, an outwardly happy demeanor, and intellectual disability. We describe a behavioral phenotype in a mouse model of Angelman syndrome and related abnormalities in prefrontal cortex function. We

  7. [Establishment and evaluation of a novel mouse model of orthotopic colon cancer in the mesenteric triangle of the cecum].

    Science.gov (United States)

    He, Xiangfeng; Shi, Wen; Wen, Song; Sun, Yongqiang; Ling, Guojie; Shen, Kang; Peng, Chunlei; Chen, Baoan; Wang, Jianhong

    2015-06-01

    To explore the feasibility of preparation of a mouse model of orthotopic colon cancer by injecting tumor cell suspension into mesenteric triangle of the cecum. Twenty SPF 8-week old BALB/c mice (male:female = 1:1) were used in this study. The mouse caecum was exposed by laparostomy, and suspension of mouse colon adenocarcinoma CT26. WT cells was injected into the mesenteric triangle of cecum for preparation of a mouse model of orthotopic colon cancer. Mouse orthotopic colon cancer was developed by injection of tumor cell suspension into mesenteric triangle of the cecum showing a successful rate of 100%, without intestinal obstruction, and the liver, spleen, diaphragm and mesenteric lymph nodes metastasis rates were high in all the 20 experimental mice. The establishment of mouse models of orthotopic colon cancer by injection of tumor cell suspension into the mesenteric triangle is a simple, rapid, and easy to master procedure, causing less damage to the colon wall, safe and with less trauma to the mice. This method may provide an ideal mouse model of orthotopic colon cancer for the study of pathogenesis as well as liver metastasis mechanisms of colon cancer.

  8. Normal social seeking behavior, hypoactivity and reduced exploratory range in a mouse model of Angelman syndrome

    Directory of Open Access Journals (Sweden)

    Reiter Lawrence T

    2011-01-01

    Full Text Available Abstract Background Angelman syndrome (AS is a neurogenetic disorder characterized by severe developmental delay with mental retardation, a generally happy disposition, ataxia and characteristic behaviors such as inappropriate laughter, social-seeking behavior and hyperactivity. The majority of AS cases are due to loss of the maternal copy of the UBE3A gene. Maternal Ube3a deficiency (Ube3am-/p+, as well as complete loss of Ube3a expression (Ube3am-/p-, have been reproduced in the mouse model used here. Results Here we asked if two characteristic AS phenotypes - social-seeking behavior and hyperactivity - are reproduced in the Ube3a deficient mouse model of AS. We quantified social-seeking behavior as time spent in close proximity to a stranger mouse and activity as total time spent moving during exploration, movement speed and total length of the exploratory path. Mice of all three genotypes (Ube3am+/p+, Ube3am-/p+, Ube3am-/p- were tested and found to spend the same amount of time in close proximity to the stranger, indicating that Ube3a deficiency in mice does not result in increased social seeking behavior or social dis-inhibition. Also, Ube3a deficient mice were hypoactive compared to their wild-type littermates as shown by significantly lower levels of activity, slower movement velocities, shorter exploratory paths and a reduced exploratory range. Conclusions Although hyperactivity and social-seeking behavior are characteristic phenotypes of Angelman Syndrome in humans, the Ube3a deficient mouse model does not reproduce these phenotypes in comparison to their wild-type littermates. These phenotypic differences may be explained by differences in the size of the genetic defect as ~70% of AS patients have a deletion that includes several other genes surrounding the UBE3A locus.

  9. Calea zacatechichi dichloromethane extract exhibits antidiarrheal and antinociceptive effects in mouse models mimicking irritable bowel syndrome.

    Science.gov (United States)

    Sałaga, M; Kowalczuk, A; Zielinska, M; Błażewicz, A; Fichna, J

    2015-10-01

    Calea zacatechichi Schltdl. (Asteraceae alt. Compositae) is a Mexican plant commonly used in folk medicine to treat respiratory and gastrointestinal (GI) disorders. The objective of this study is to characterize the effect of C. zacatechichi extracts in mouse models mimicking the symptoms of irritable bowel syndrome (IBS). Powdered C. zacatechichi herb (leaves, stems, and flowers) was extracted with methanol. Methanolic extract was filtered and evaporated giving methanolic fraction. The residue was extracted with dichloromethane (DCM). Methanolic and DCM (200 mg/kg, per os) extracts were screened for their effect on GI motility in several in vitro tests, and the antidiarrheal and antinociceptive effects were assessed using mouse models. The influence of the DCM extract on motoric parameters and exploratory behaviors was also assessed. Finally, the composition of C. zacatechichi DCM extract was qualitatively analyzed using liquid chromatography-mass spectrometry (LC-MS) method. C. zacatechichi DCM extract significantly inhibited the contractility of mouse colon in vitro (IC50 = 17 ± 2 μg/ml). Administration of the DCM extract in vivo (200 mg/kg, per os) significantly prolonged the time of whole GI transit (46 ± 1 vs. 117 ± 27 min for control and DCM-treated animals, respectively; P = 0.0023), inhibited hypermotility, and reduced pain in mouse models mimicking functional GI disorders. Our findings suggest that constituents of the C. zacatechichi DCM extract exhibit antidiarrheal and analgesic activity. The extract may thus become an attractive material for isolation of compounds that may be used as a supplementary treatment for pain and diarrhea associated with IBS in the future.

  10. An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria.

    NARCIS (Netherlands)

    Andressoo, Jaan-Olle; Mitchell, James R; Wit, Jan de; Hoogstraten, Deborah; Volker, Marcel; Toussaint, Wendy; Speksnijder, Ewoud; Beems, Rudolf B; Steeg, Harry van; Jans, Judith; Zeeuw, Chris I de; Jaspers, Nicolaas G J; Raams, Anja; Lehmann, Alan R; Vermeulen, Wim; Hoeijmakers, Jan H J; Horst, Gijsbertus T J van der

    2006-01-01

    Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the

  11. Genetically engineered Lactococcus lactis protect against house dust mite allergy in a BALB/c mouse model

    National Research Council Canada - National Science Library

    Ai, Chunqing; Zhang, Qiuxiang; Ren, Chengcheng; Wang, Gang; Liu, Xiaoming; Tian, Fengwei; Zhao, Jianxin; Zhang, Hao; Chen, Yong Q; Chen, Wei

    2014-01-01

    .... Therefore, we sought to investigate how recombinant major dust mite allergen Der p2-expressing Lactococcus lactis as a mucosal vaccine induced the immune tolerance against house dust mite allergy in a mouse model...

  12. Anticancer and cytotoxic properties of the latex of Calotropis procera in a transgenic mouse model of hepatocellular carcinoma

    OpenAIRE

    Choedon, Tenzin; Mathan, Ganeshan; Arya, Soneera; Kumar, Vijay L.; Kumar, Vijay

    2006-01-01

    AIM: To evaluate the anticancer property of the dried latex (DL) of Calotropis procera, a tropical medicinal plant, in the X15-myc transgenic mouse model of hepatocellular carcinoma and to elucidate its mechanism of action in cell culture.

  13. Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection

    National Research Council Canada - National Science Library

    Guedes-da-Silva, F H; Batista, D G J; da Silva, C F; Meuser, M B; Simões-Silva, M R; de Araújo, J S; Ferreira, C G; Moreira, O C; Britto, C; Lepesheva, G I; Soeiro, Maria de Nazaré C

    2015-01-01

    ...) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes...

  14. Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy

    National Research Council Canada - National Science Library

    Bäumer, Dirk; Lee, Sheena; Nicholson, George; Davies, Joanna L; Parkinson, Nicholas J; Murray, Lyndsay M; Gillingwater, Thomas H; Ansorge, Olaf; Davies, Kay E; Talbot, Kevin

    2009-01-01

    .... Widespread splicing abnormalities have recently been reported at end-stage in a mouse model of SMA, leading to the proposition that disruption of efficient splicing is the primary mechanism of motor neuron death...

  15. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy

    National Research Council Canada - National Science Library

    Iba, Michiyo; Guo, Jing L; McBride, Jennifer D; Zhang, Bin; Trojanowski, John Q; Lee, Virginia M-Y

    2013-01-01

    ...) comprising filamentous tau protein. Although emerging evidence suggests that tau pathology may be transmitted, we demonstrate here that synthetic tau fibrils are sufficient to transmit tau inclusions in a mouse model...

  16. Heat-induced structural changes affect OVA-antigen processing and reduce allergic response in mouse model of food allergy

    National Research Council Canada - National Science Library

    Golias, Jaroslav; Schwarzer, Martin; Wallner, Michael; Kverka, Miloslav; Kozakova, Hana; Srutkova, Dagmar; Klimesova, Klara; Sotkovsky, Petr; Palova-Jelinkova, Lenka; Ferreira, Fatima; Tuckova, Ludmila

    2012-01-01

    The egg protein ovalbumin (OVA) belongs to six most frequent food allergens. We investigated how thermal processing influences its ability to induce allergic symptoms and immune responses in mouse model of food allergy...

  17. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models.

    Science.gov (United States)

    Lengyel, Ernst; Litchfield, Lacey M; Mitra, Anirban K; Nieman, Kristin M; Mukherjee, Abir; Zhang, Yilin; Johnson, Alyssa; Bradaric, Michael; Lee, WooSeok; Romero, Iris L

    2015-04-01

    There is increasing preclinical evidence indicating that metformin, a medication commonly used for type 2 diabetes mellitus, may protect against cancer. Motivated by this emerging evidence we asked 2 questions: (1) can metformin prevent ovarian cancer growth by altering metabolism and (2) will metformin increase sensitivity to chemotherapy. The effect of metformin in ovarian cancer was tested in vitro and with 2 different mouse models. In vitro, cell lines (n = 6) were treated with metformin (10-40 mmol/L) or phosphate-buffered saline solution and cellular proliferation and metabolic alterations (adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis) were compared between the 2 groups. In mouse models, a prevention study was performed by treating mice with metformin (250 mg/kg/d intraperitoneally) or placebo for 2 weeks followed by intraperitoneal injection of the SKOV3ip1 human ovarian cancer cell line, and the mean number of tumor implants in each treatment group was compared. In a treatment study, the LSL-K-ras(G12D/+)/PTEN(floxP/floxP) genetic mouse model of ovarian cancer was used. Mice were treated with placebo, paclitaxel (3 mg/kg/wk intraperitoneally for 7 weeks), metformin (100 mg/kg/d in water for 7 weeks), or paclitaxel plus metformin, and tumor volume was compared among treatment groups. In vitro, metformin decreased proliferation of ovarian cancer cell lines and induced cell cycle arrest, but not apoptosis. Further analysis showed that metformin altered several aspects of metabolism including adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis. In the prevention mouse model, mice that were pretreated with metformin had 60% fewer tumor implants compared with controls (P cancer cells, prevents tumor growth, and increases sensitivity to chemotherapy in vitro and in mouse models. These preclinical findings suggest that metformin warrants further investigation for use as an

  18. Generation and characterization of an inducible transgenic model for studying mouse esophageal biology

    Directory of Open Access Journals (Sweden)

    Roth Sabrina

    2012-06-01

    Full Text Available Abstract Background To facilitate the in vivo study of esophageal (stem cell biology in homeostasis and cancer, novel mouse models are necessary to elicit expression of candidate genes in a tissue-specific and inducible fashion. To this aim, we developed and studied a mouse model to allow labeling of esophageal cells with the histone 2B-GFP (H2B-GFP fusion protein. Results First, we generated a transgenic mouse model expressing the reverse tetracycline transactivator rtTA2-M2 under control of the promoter (ED-L2 of the Epstein-Barr virus (EBV gene encoding the latent membrane protein-1 (LMP-1. The newly generated ED-L2-rtTA2-M2 (ED-L2-rtTA mice were then bred with the previously developed tetO-HIST1H2BJ/GFP (tetO-H2B-GFP model to assess inducibility and tissue-specificity. Expression of the H2B-GFP fusion protein was observed upon doxycycline induction but was restricted to the terminally differentiated cells above the basal cell layer. To achieve expression in the basal compartment of the esophagus, we subsequently employed a different transgenic model expressing the reverse transactivator rtTA2S-M2 under the control of the ubiquitous, methylation-free CpG island of the human hnRNPA2B1-CBX3 gene (hnRNP-rtTA. Upon doxycycline administration to the compound hnRNP-rtTA/tetO-H2B-GFP mice, near-complete labeling of all esophageal cells was achieved. Pulse-chase experiments confirmed that complete turnover of the esophageal epithelium in the adult mouse is achieved within 7–10 days. Conclusions We show that the esophagus-specific promoter ED-L2 is expressed only in the differentiated cells above the basal layer. Moreover, we confirmed that esophageal turn-over in the adult mouse does not exceed 7–10 days.

  19. TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy

    Directory of Open Access Journals (Sweden)

    Ansorge Olaf

    2008-10-01

    Full Text Available Abstract Background Redistribution of nuclear TAR DNA binding protein 43 (TDP-43 to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA. Results TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords. Conclusion These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.

  20. Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer.

    Science.gov (United States)

    Parisi, T; Bronson, R T; Lees, J A

    2015-11-26

    The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that the loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to the age of onset, histological appearance, invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rb-deficient tumors demonstrate genomic instability and they show activation of β-catenin. Deregulation of the Wnt/β-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of β-catenin was observed in the neuroendocrine tumors. To date, attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation.

  1. Quantitative 3D investigation of Neuronal network in mouse spinal cord model.

    Science.gov (United States)

    Bukreeva, I; Campi, G; Fratini, M; Spanò, R; Bucci, D; Battaglia, G; Giove, F; Bravin, A; Uccelli, A; Venturi, C; Mastrogiacomo, M; Cedola, A

    2017-01-23

    The investigation of the neuronal network in mouse spinal cord models represents the basis for the research on neurodegenerative diseases. In this framework, the quantitative analysis of the single elements in different districts is a crucial task. However, conventional 3D imaging techniques do not have enough spatial resolution and contrast to allow for a quantitative investigation of the neuronal network. Exploiting the high coherence and the high flux of synchrotron sources, X-ray Phase-Contrast multiscale-Tomography allows for the 3D investigation of the neuronal microanatomy without any aggressive sample preparation or sectioning. We investigated healthy-mouse neuronal architecture by imaging the 3D distribution of the neuronal-network with a spatial resolution of 640 nm. The high quality of the obtained images enables a quantitative study of the neuronal structure on a subject-by-subject basis. We developed and applied a spatial statistical analysis on the motor neurons to obtain quantitative information on their 3D arrangement in the healthy-mice spinal cord. Then, we compared the obtained results with a mouse model of multiple sclerosis. Our approach paves the way to the creation of a "database" for the characterization of the neuronal network main features for a comparative investigation of neurodegenerative diseases and therapies.

  2. AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia.

    Directory of Open Access Journals (Sweden)

    Ji-jing Pang

    Full Text Available Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3 are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia.

  3. Quantitative 3D investigation of Neuronal network in mouse spinal cord model

    Science.gov (United States)

    Bukreeva, I.; Campi, G.; Fratini, M.; Spanò, R.; Bucci, D.; Battaglia, G.; Giove, F.; Bravin, A.; Uccelli, A.; Venturi, C.; Mastrogiacomo, M.; Cedola, A.

    2017-01-01

    The investigation of the neuronal network in mouse spinal cord models represents the basis for the research on neurodegenerative diseases. In this framework, the quantitative analysis of the single elements in different districts is a crucial task. However, conventional 3D imaging techniques do not have enough spatial resolution and contrast to allow for a quantitative investigation of the neuronal network. Exploiting the high coherence and the high flux of synchrotron sources, X-ray Phase-Contrast multiscale-Tomography allows for the 3D investigation of the neuronal microanatomy without any aggressive sample preparation or sectioning. We investigated healthy-mouse neuronal architecture by imaging the 3D distribution of the neuronal-network with a spatial resolution of 640 nm. The high quality of the obtained images enables a quantitative study of the neuronal structure on a subject-by-subject basis. We developed and applied a spatial statistical analysis on the motor neurons to obtain quantitative information on their 3D arrangement in the healthy-mice spinal cord. Then, we compared the obtained results with a mouse model of multiple sclerosis. Our approach paves the way to the creation of a “database” for the characterization of the neuronal network main features for a comparative investigation of neurodegenerative diseases and therapies.

  4. Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

    Directory of Open Access Journals (Sweden)

    Simone B Sartori

    Full Text Available The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB, or normal (NAB anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α(2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i for identifying biological factors underlying misguided conditioned fear responses and (ii for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

  5. Preclinical transfusion-dependent humanized mouse model of beta thalassemia major.

    Science.gov (United States)

    Huo, Yongliang; McConnell, Sean C; Ryan, Thomas M

    2009-05-07

    A preclinical humanized mouse model of beta thalassemia major or Cooley anemia (CA) was generated by targeted gene replacement of the mouse adult globin genes in embryonic stem cells. The mouse adult alpha and beta globin genes were replaced with adult human alpha globin genes (alpha2alpha1) and a human fetal to adult hemoglobin (Hb)-switching cassette (gamma(HPFH)deltabeta(0)), respectively. Similar to human infants with CA, fully humanized mice survived postnatally by synthesizing predominantly human fetal Hb, HbF (alpha(2)gamma(2)), with a small amount of human minor adult Hb, HbA2 (alpha(2)delta(2)). Completion of the human fetal to adult Hb switch after birth resulted in severe anemia marked by erythroid hyperplasia, ineffective erythropoiesis, hemolysis, and death. Similar to human patients, CA mice were rescued from lethal anemia by regular blood transfusion. Transfusion corrected the anemia and effectively suppressed the ineffective erythropoiesis, but led to iron overload. This preclinical humanized animal model of CA will be useful for the development of new transfusion and iron chelation regimens, the study of iron homeostasis in disease, and testing of cellular and genetic therapies for the correction of thalassemia.

  6. Curly tail: a 50 year history of the mouse spina bifida model

    Science.gov (United States)

    van Straaten, Henny W.M.; Copp, Andrew J.

    2014-01-01

    Summary This paper reviews 50 years of progress towards understanding the aetiology and pathogenesis of neural tube defects (NTD) in the curly tail (ct) mutant mouse. More than 45 papers have been published on various aspects of curly tail with the result that it is now the best understood mouse model of NTD pathogenesis. The failure of closure of the spinal neural tube, which leads to spina bifida in this mouse, has been traced back to a tissue-specific defect of cell proliferation in the tail bud of the E9.5 embryo. This cell proliferation defect results in a growth imbalance in the caudal region that generates ventral curvature of the body axis. Neurulation movements are opposed, leading to delayed neuropore closure and spina bifida, or tail defects. It is interesting to reflect that these advances have been achieved in the absence of information on the nature of the ct gene product, which remains unidentified. In addition to the principal ct gene, which maps to distal Chromosome 4, the curly tail phenotype is influenced by several modifier genes and by environmental factors. NTD in curly tail are resistant to folic acid, but can be prevented by myo-inositol. These and other features of NTD in this system bear striking similarities to the situation in humans, making curly tail a model for understanding a sub-type of human NTD. PMID:11396850

  7. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

    Directory of Open Access Journals (Sweden)

    Nina Fransén-Pettersson

    Full Text Available Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

  8. Proteomic profiling of the hypothalamus in two mouse models of narcolepsy.

    Science.gov (United States)

    Azzam, Sausan; Schlatzer, Daniela; Nethery, David; Saleh, Dania; Li, Xiaolin; Akladious, Afaf; Chance, Mark R; Strohl, Kingman P

    2017-07-01

    Narcolepsy is a disabling neurological disorder of sleepiness linked to the loss of neurons producing orexin neuropeptides in the hypothalamus. Two well-characterized phenotypic mouse models of narcolepsy, loss-of-function (orexin-knockout), and progressive loss of orexin (orexin/ataxin-3) exist. The open question is whether the proteomics signatures of the hypothalamus would be different between the two models. To address this gap, we utilized a label-free proteomics approach and conducted a hypothalamic proteome analysis by comparing each disease model to that of wild type. Following data processing and statistical analysis, 14 484 peptides mapping to 2282 nonredundant proteins were identified, of which 39 proteins showed significant differences in protein expression across groups. Altered proteins in both models showed commonalties in pathways for mitochondrial dysfunction and neuronal degeneration, as well as altered proteins related to inflammatory demyelination, insulin resistance, metabolic responses, and the dopaminergic and monoaminergic systems. Model-specific alterations in insulin degraded enzyme (IDE) and synaptosomal-associated protein-25 were unique to orexin-KO and orexin/ataxin-3, respectively. For both models, proteomics not only identified clinically suspected consequences of orexin loss on energy homeostasis and neurotransmitter systems, but also identified commonalities in inflammation and degeneration despite the entirely different genetic basis of the two mouse models. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Comparison and evaluation of two different methods to establish the cigarette smoke exposure mouse model of COPD

    OpenAIRE

    Shu, Jiaze; Li, Defu; Ouyang, Haiping; Huang, Junyi; Long, Zhen; Liang, Zhihao; Chen, Yuqin; Chen, Yiguan; Zheng, Qiuyu; Kuang, Meidan; Tang, Haiyang; Wang, Jian; Lu, Wenju

    2017-01-01

    Animal model of cigarette smoke (CS) –induced chronic obstructive pulmonary disease (COPD) is the primary testing methodology for drug therapies and studies on pathogenic mechanisms of disease. However, researchers have rarely run simultaneous or side-by-side tests of whole-body and nose-only CS exposure in building their mouse models of COPD. We compared and evaluated these two different methods of CS exposure, plus airway Lipopolysaccharides (LPS) inhalation, in building our COPD mouse mode...

  10. Analgesic effects of lappaconitine in leukemia bone pain in a mouse model

    Directory of Open Access Journals (Sweden)

    Xiao-Cui Zhu

    2015-05-01

    Full Text Available Bone pain is a common and severe symptom in cancer patients. The present study employed a mouse model of leukemia bone pain by injection K562 cells into tibia of mouse to evaluate the analgesic effects of lappacontine. Our results showed that the lappaconitine treatment at day 15, 17 and 19 could effectively reduce the spontaneous pain scoring values, restore reduced degree in the inclined-plate test induced by injection of K562 cells, as well as restore paw mechanical withdrawal threshold and paw withdrawal thermal latency induced by injection of K562 cells to the normal levels. Additionally, the molecular mechanisms of lappaconitine’s analgesic effects may be related to affect the expression levels of endogenous opioid system genes (POMC, PENK and MOR, as well as apoptosis-related genes (Xiap, Smac, Bim, NF-κB and p53. Our present results indicated that lappaconitine may become a new analgesic agent for leukemia bone pain management.

  11. A decerebrate adult mouse model for examining the sensorimotor control of locomotion.

    Science.gov (United States)

    Nakanishi, Stan T; Whelan, Patrick J

    2012-01-01

    As wild-type and genetically modified mice are progressively becoming the predominant models for studying locomotor physiology, the technical ability to record sensory and motor components from adult mice, in vivo, are expected to contribute to a better understanding of sensorimotor spinal cord networks. Here, specific technical and surgical details are presented on how to produce an adult decerebrate mouse preparation that can reliably produce sustained bouts of stepping, in vivo, in the absence of anesthetic drugs. Data are presented demonstrating the ability of this preparation to produce stepping during treadmill locomotion, adaptability in its responses to changes in the treadmill speed, and left-right alternation. Furthermore, intracellular recordings from motoneurons and interneurons in the spinal cord are presented from preparations where muscle activity was blocked. Intraaxonal recordings are also presented demonstrating that individual afferents can be recorded using this preparation. These data demonstrate that the adult decerebrate mouse is a tractable preparation for the study of sensorimotor systems.

  12. Vertical transmission of bovine spongiform encephalopathy prions evaluated in a transgenic mouse model.

    Science.gov (United States)

    Castilla, J; Brun, A; Díaz-San Segundo, F; Salguero, F J; Gutiérrez-Adán, A; Pintado, B; Ramírez, M A; del Riego, L; Torres, J M

    2005-07-01

    In this work we show evidence of mother-to-offspring transmission in a transgenic mouse line expressing bovine PrP (boTg) experimentally infected by intracerebral administration of bovine spongiform encephalopathy (BSE) prions. PrP(res) was detected in brains of newborns from infected mothers only when mating was allowed near to the clinical stage of disease, when brain PrP(res) deposition could be detected by Western blot analysis. Attempts to detect infectivity in milk after intracerebral inoculation in boTg mice were unsuccessful, suggesting the involvement of other tissues as carriers of prion dissemination. The results shown here prove the ability of BSE prions to spread centrifugally from the central nervous system to peripheral tissues and to offspring in a mouse model. Also, these results may complement previous epidemiological data supporting the occurrence of vertical BSE transmission in cattle.

  13. Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Mathews, K.D.; Rapisarda, D.; Bailey, H.L. [Univ. of Iowa College of Medicine, Iowa City, IA (United States)] [and others

    1995-07-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distalmost portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD. 28 refs., 4 figs.

  14. A mouse model of breast cancer metastasis to the choroid of the eye.

    Science.gov (United States)

    Kuhn, Misty; Shah, Sarah; Natasha, Tajneen; Rittling, Susan R

    2005-01-01

    Transformed mouse mammary epithelial cells, r3T, injected into the arterial circulation form bone metastases with high frequency. Here we report that metastases to the choroid of the eye also occur in these mice with a penetrance of at least 50%. The tumors can occupy as much as half the volume of the eye, and pigmented cells become incorporated into and distributed throughout the tumors. Pigmentation is also observed in the brains and optic nerves of mice with choroidal tumors, suggesting that the tumor cells stimulate migration of pigmented cells along the optic nerve into the brain. To our knowledge, this is the first mouse model of breast cancer choroidal metastasis, and should be useful in the study of this disease.

  15. Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Yoke-Chen; Wang, James D. [Rutgers University, Pharmacology and Toxicology, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States); Svoboda, Kathy K. [Texas A and M University, Baylor College of Dentistry, Center for Craniofacial Research 3302 Gaston Ave, Dallas, Texas 75246 (United States); Casillas, Robert P. [MRIGlobal, 425 Volker Boulevard, Kansas City, MO 64110 (United States); Laskin, Jeffrey D. [UMDNJ-Robert Wood Johnson Medical School, Environmental and Occupational Medicine, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States); Gordon, Marion K. [Rutgers University, Pharmacology and Toxicology, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States); Gerecke, Donald R., E-mail: gerecke@eohsi.rutgers.edu [Rutgers University, Pharmacology and Toxicology, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States)

    2013-04-15

    The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin γ2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing from 24 h to 168 h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin γ2 and GRP78/BIP, showed colocalization of the two molecules 72 h post exposure indicating that the laminin γ2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24 h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury. - Highlights: ► We demonstrated ER stress response in the mouse ear vesicant model. ► We described the asymmetrical nature of wound repair in the MEVM. ► We identified the distribution of various ER stress markers in the MEVM.

  16. Expression of Caytaxin protein in Cayman Ataxia mouse models correlates with phenotype severity.

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    Kristine M Sikora

    Full Text Available Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcay(jit (jittery and Atcay(swd (sidewinder mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcay(ji-hes (hesitant line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin's physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin's role in maintaining normal neuronal function.

  17. Efficacy of tomato concentrates in mouse models of dyslipidemia and cancer.

    Science.gov (United States)

    Chattopadhyay, Arnab; Grijalva, Victor; Hough, Greg; Su, Feng; Mukherjee, Pallavi; Farias-Eisner, Robin; Anantharamaiah, G M; Faull, Kym F; Hwang, Lin H; Navab, Mohamad; Fogelman, Alan M; Reddy, Srinivasa T

    2015-08-01

    We previously reported that adding freeze-dried tomato powder from transgenic plants expressing the apolipoprotein A-I mimetic peptide 6F at 2.2% by weight to a Western diet (WD) ameliorated dyslipidemia and atherosclerosis in mice. The same dose in a human would require three cups of tomato powder three times daily. To reduce the volume, we sought a method to concentrate 6F. Remarkably, extracting the transgenic freeze-dried tomato overnight in ethyl acetate with 5% acetic acid resulted in a 37-fold reduction in the amount of transgenic tomato needed for biologic activity. In a mouse model of dyslipidemia, adding 0.06% by weight of the tomato concentrate expressing the 6F peptide (Tg6F) to a WD significantly reduced plasma total cholesterol and triglycerides (P tomato concentrate (EV), to standard mouse chow reduced tumor-associated neutrophils by 94 ± 1.1% (P = 0.0052), and reduced tumor burden by two-thirds (P = 0.0371). Adding 0.06% of either EV or Tg6F by weight to standard mouse chow significantly reduced tumor burden in a mouse model of ovarian cancer; however, Tg6F was significantly more effective (35% reduction for EV vs. 53% reduction for Tg6F; P = 0.0069). Providing the same dose of tomato concentrate to humans would require only two tablespoons three times daily making this a practical approach for testing oral apoA-I mimetic therapy in the treatment of dyslipidemia and cancer.

  18. An athymic mouse model to mimic cobalt-60 cutaneous radiation injury

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    Mosca, Rodrigo Crespo; Ferreira, Danilo Cardenuto; Napolitano, Celia Marina; Santin, Stefany Plumeri; Dornelles, Leonardo Dalla Porta; Alvarenga, Eluara Ortigoso; Mathor, Monica Beatriz, E-mail: rcmosca@usp.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2013-07-01

    Propose: Cutaneous wound from irradiation is the most common complication in radiotherapy treatment, and can be lead to mortality. We describe an athymic mouse model to mimic cutaneous radiation injury by Cobalt-60. Methods: A protocol was including dosimetry with silicon diodes,10x10x5 cm arrangement made by four lead bricks and PVC pipe designed to immobilize the athymic mouse in order to irradiate one clamped back skin point that was subdivided in four parts. To get the measurements of dose rates on the arrangement in Panoramic Irradiator, it was used a silicon diode encased in an opaque protection for ambient light and connected to an electric cable, forming a dosing probe. The currents generated in diode sensitive volume as a function of time of exposure to gamma radiation coming from the radiator, with dose rate of 0,015 Gy/min in positions 1, 0,021 Gy/min in position 2, 0,55 Gy/min in position 3 and 1,45 Gy/min in position four. After the dosimetry, each athymic mouse was anesthetized using Xylazine and Ketamine dilution and entered into a PVC pipe and a small portion of skin (1 cm{sup 3}) was clamped. This tube was then fixed to arrangement and the athymic mouse was irradiate for 60 min, than it was being returned to its cage. Results: The wound was visualized in all animals and photographed after 5 days of irradiation, with the emergence of ulceration after 9 days. No systemic or lethal sequelae occurred or visualized in any animals. Late clinical signs included a wound healing after 22 days. Conclusion: While still being a baseline study, we created a new functional preclinical animal model that can be used for new therapies and may improve radiotherapy management. (author)

  19. Instability of the insertional mutation in CftrTgH(neoimHgu cystic fibrosis mouse model

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    Dorin Julia R

    2004-04-01

    Full Text Available Abstract Background A major boost to the cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original CftrTgH(neoimHgu CF mouse model we have generated using strict brother × sister mating two inbred CftrTgH(neoimHgu mouse lines (CF/1 and CF/3. Thereafter, the insertional mutation was introgressed from CF/3 into three inbred backgrounds (C57BL/6, BALB/c, DBA/2J generating congenic animals. In every backcross cycle germline transmission of the insertional mutation was monitored by direct probing the insertion via Southern RFLP. In order to bypass this time consuming procedure we devised an alternative PCR based protocol whereby mouse strains are differentiated at the Cftr locus by Cftr intragenic microsatellite genotypes that are tightly linked to the disrupted locus. Results Using this method we were able to identify animals carrying the insertional mutation based upon the differential haplotypic backgrounds of the three inbred strains and the mutant CftrTgH(neoimHgu at the Cftr locus. Moreover, this method facilitated the identification of the precise vector excision from the disrupted Cftr locus in two out of 57 typed animals. This reversion to wild type status took place without any loss of sequence revealing the instability of insertional mutations during the production of congenic animals. Conclusions We present intragenic microsatellite markers as a tool for fast and efficient identification of the introgressed locus of interest in the recipient strain during congenic animal breeding. Moreover, the same genotyping method allowed the identification of a vector excision event, posing questions on the stability of insertional mutations in mice.

  20. Cytomegalovirus-induced embryopathology: mouse submandibular salivary gland epithelial-mesenchymal ontogeny as a model

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    Huang Jing

    2006-09-01

    Full Text Available Abstract Background Human studies suggest, and mouse models clearly demonstrate, that cytomegalovirus (CMV is dysmorphic to early organ and tissue development. CMV has a particular tropism for embryonic salivary gland and other head mesenchyme. CMV has evolved to co-opt cell signaling networks so to optimize replication and survival, to the detriment of infected tissues. It has been postulated that mesenchymal infection is the critical step in disrupting organogenesis. If so, organogenesis dependent on epithelial-mesenchymal interactions would be particularly vulnerable. In this study, we chose to model the vulnerability by investigating the cell and molecular pathogenesis of CMV infected mouse embryonic submandibular salivary glands (SMGs. Results We infected E15 SMG explants with mouse CMV (mCMV. Active infection for up to 12 days in vitro results in a remarkable cell and molecular pathology characterized by atypical ductal epithelial hyperplasia, apparent epitheliomesenchymal transformation, oncocytic-like stromal metaplasia, β-catenin nuclear localization, and upregulation of Nfkb2, Relb, Il6, Stat3, and Cox2. Rescue with an antiviral nucleoside analogue indicates that mCMV replication is necessary to initiate and maintain SMG dysmorphogenesis. Conclusion mCMV infection of embryonic mouse explants results in dysplasia, metaplasia, and, possibly, anaplasia. The molecular pathogenesis appears to center around the activation of canonical and, perhaps more importantly, noncanonical NFκB. Further, COX-2 and IL-6 are important downstream effectors of embryopathology. At the cellular level, there appears to be a consequential interplay between the transformed SMG cells and the surrounding extracellular matrix, resulting in the nuclear translocation of β-catenin. From these studies, a tentative framework has emerged within which additional studies may be planned and performed.

  1. Dmdmdx/Largemyd: a new mouse model of neuromuscular diseases useful for studying physiopathological mechanisms and testing therapies

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    Poliana C. M. Martins

    2013-09-01

    Although muscular dystrophies are among the most common human genetic disorders, there are few treatment options available. Animal models have become increasingly important for testing new therapies prior to entering human clinical trials. The Dmdmdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD, presenting the same molecular and protein defect as seen in humans with the disease. However, this mouse is not useful for clinical trials because of its very mild phenotype. The mouse model for congenital myodystrophy type 1D, Largemyd, harbors a mutation in the glycosyltransferase Large gene and displays a severe phenotype. To help elucidate the role of the proteins dystrophin and LARGE in the organization of the dystrophin-glycoprotein complex in muscle sarcolemma, we generated double-mutant mice for the dystrophin and LARGE proteins. The new Dmdmdx/Largemyd mouse model is viable and shows a severe phenotype that is associated with the lack of dystrophin in muscle. We tested the usefulness of our new mouse model for cell therapy by systemically injecting them with normal murine mesenchymal adipose stem cells (mASCs. We verified that the mASCs were hosted in the dystrophic muscle. The new mouse model has proven to be very useful for the study of several other therapies, because injected cells can be screened both through DNA and protein analysis. Study of its substantial muscle weakness will also be very informative in the evaluation of functional benefits of these therapies.

  2. Similarity on neural stem cells and brain tumor stem cells in transgenic brain tumor mouse models

    OpenAIRE

    Qiao, Guanqun; Li, Qingquan; Peng, Gang; Ma, Jun; Fan, Hongwei; Li, Yingbin

    2013-01-01

    Although it is believed that glioma is derived from brain tumor stem cells, the source and molecular signal pathways of these cells are still unclear. In this study, we used stable doxycycline-inducible transgenic mouse brain tumor models (c-myc+/SV40Tag+/Tet-on+) to explore the malignant trans-formation potential of neural stem cells by observing the differences of neural stem cells and brain tumor stem cells in the tumor models. Results showed that chromosome instability occurred in brain t...

  3. The efficacy of nerve growth factor antibody in a mouse model of neuropathic cancer pain

    OpenAIRE

    Miyagi, Masayuki; Ishikawa, Tetsuhiro; KAMODA, Hiroto; Suzuki, Miyako; Inoue, Gen; Sakuma, Yoshihiro; Oikawa, Yasuhiro; Uchida,Kentaro; SUZUKI, Takane; Takahashi, Kazuhisa; Takaso, Masashi; Ohtori, Seiji

    2016-01-01

    Neuropathic cancer pain is caused by tumors compressing the spinal nerve roots and is usually difficult to treat. The aim of current study was to determine the influence of NGF antibody on pain-related markers and behavior in a mouse model of neuropathic cancer pain. Twenty mice were used to model neuropathic cancer pain by applying murine sarcoma cells to their left sciatic nerve. Ten mice were sham operated. Two weeks after surgery, the murine sarcoma-affected mice were allocated randomly i...

  4. The db/db Mouse : a Useful Model for the Study of Diabetic Retinal Neurodegeneration

    OpenAIRE

    Patricia Bogdanov; Lidia Corraliza; Josep A. Villena; Andrea R Carvalho; José Garcia-Arumí; David Ramos; Jesús Ruberte; Rafael Simó; Cristina Hernández

    2014-01-01

    BACKGROUND: To characterize the sequential events that are taking place in retinal neurodegeneration in a murine model of spontaneous type 2 diabetes (db/db mouse). METHODS: C57BLKsJ-db/db mice were used as spontaneous type 2 diabetic animal model, and C57BLKsJ-db/+ mice served as the control group. To assess the chronological sequence of the abnormalities the analysis was performed at different ages (8, 16 and 24 weeks). The retinas were evaluated in terms of morphological and functional abn...

  5. The mouse/human cross-species heterodimer of leucine-rich repeat kinase 2: possible significance in the transgenic model mouse of Parkinson's disease.

    Science.gov (United States)

    Miyajima, T; Ohta, E; Kawada, H; Maekawa, T; Obata, F

    2015-02-19

    Leucine-rich repeat kinase (LRRK2) is the causal molecule of autosomal dominant Parkinson's disease (PD). We previously reported that intracellular degradation of wild-type (WT) LRRK2 is promoted by formation of heterodimers with the I2020T mutant LRRK2. In the present study, we investigated whether this is also the case for mouse/human cross-species heterodimers, which could be formed in transgenic mice. First, by co-transfection and immunoprecipitation, we identified the cross-species heterodimer of mouse LRRK2 and human LRRK2. Next, we found that the protein level of mouse LRRK2 decreased when co-transfected with human I2020T LRRK2, but not with human WT LRRK2. These results suggested that degradation of mouse LRRK2 was promoted by formation of a cross-species heterodimer with the mutant LRRK2. In I2020T LRRK2-transgenic mice, the lower protein level of brain LRRK2 in comparison with control mice, together with higher expression of the mRNA, suggested that endogenous LRRK2 was degraded by formation of cross-species heterodimers. Our results suggest a new concept of cross-species dimer/oligomer formation in transgenic disease-model mice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. Mouse Models for the Study of Mucosal Vaccination Against Otitis Media

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    Sabirov, Albert; Metzger, Dennis W.

    2008-01-01

    Otitis media (OM) is one of the most common infectious diseases in humans. The pathogenesis of OM involves nasopharyngeal colonization (NP) and retrograde ascension of the pathogen up the Eustachian tube into the middle ear (ME). Due to increasing rates of antibiotic resistance, there is an urgent need for vaccines to prevent infections caused by the most common causes of bacterial OM, including nontypeable Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Current vaccine strategies aim to diminish bacterial NP carriage, thereby reducing the likelihood of developing acute OM. To be effective, vaccination should induce local mucosal mmunity both in the ME and in the NP. Studies in animal models have demonstrated that the intranasal route of vaccination is particularly effective at inducing immune responses in the nasal passage and ME for protection against OM. The mouse is increasingly used in these models, because of the availability of murine reagents and the existence of technology to manipulate murine models of disease immunologically and genetically. Previous studies confirmed the suitability of the mouse as a model for inflammatory processes in acute OM. Here, we discuss various murine models of OM and review the applicability of these models to assess the efficacy of mucosal vaccination and the mechanisms responsible for protection. In addition, we discuss various mucosal vaccine antigens, mucosal adjuvants and mucosal delivery systems. PMID:18295938

  7. Recent technological advances in using mouse models to study ovarian cancer.

    Science.gov (United States)

    House, Carrie Danielle; Hernandez, Lidia; Annunziata, Christina Messineo

    2014-01-01

    Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC.

  8. Mouse Models of Hereditary Haemorrhagic Telangiectasia: Recent Advances and Future Challenges

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    Simon eTual-Chalot

    2015-02-01

    Full Text Available Hereditary Haemorrhagic Telangiectasia (HHT is a genetic disorder characterised by a multi-systemic vascular dysplasia and haemorrhage. The precise factors leading to these vascular malformations are not yet understood and robust animal models of HHT are essential to gain a detailed understanding of the molecular and cellular events that lead to clinical symptoms, as well as to test new therapeutic modalities. Most cases of HHT are caused by mutations in either endoglin (ENG or activin receptor like kinase 1 (ACVRL1, also known as ALK1. Both genes are associated with TGFβ/BMP signalling, and loss of function mutations in the co-receptor ENG are causal in HHT1, whilst HHT2 is associated with mutations in the signalling receptor ACVRL1. Significant advances in mouse genetics have provided powerful ways to study the function of Eng and Acvrl1 in vivo, and to generate mouse models of HHT disease. Mice that are null for either Acvrl1 or Eng genes show embryonic lethality due to major defects in angiogenesis. However mice that are heterozygous for mutations in either of these genes develop to adulthood with no effect on survival. Although these heterozygous mice exhibit selected vascular phenotypes relevant to the clinical pathology of HHT, the phenotypes are variable and generally quite mild. An alternative approach using conditional knockout mice allows us to study the effects of specific inactivation of either Eng or Acvrl1 at different times in development and in different cell types. These conditional knockout mice provide robust and reproducible models of arteriovenous malformations, and they are currently being used to unravel the causal factors in HHT pathologies. In this review, we will summarize the strengths and limitations of current mouse models of HHT, discuss how knowledge obtained from these studies has already informed clinical care and explore the potential of these models for developing improved treatments for HHT patients in the

  9. Oral LD50 toxicity modeling and prediction of per- and polyfluorinated chemicals on rat and mouse.

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    Bhhatarai, Barun; Gramatica, Paola

    2011-05-01

    Quantitative structure-activity relationship (QSAR) analyses were performed using the LD(50) oral toxicity data of per- and polyfluorinated chemicals (PFCs) on rodents: rat and mouse. PFCs are studied under the EU project CADASTER which uses the available experimental data for prediction and prioritization of toxic chemicals for risk assessment by using the in silico tools. The methodology presented here applies chemometrical analysis on the existing experimental data and predicts the toxicity of new compounds. QSAR analyses were performed on the available 58 mouse and 50 rat LD(50) oral data using multiple linear regression (MLR) based on theoretical molecular descriptors selected by genetic algorithm (GA). Training and prediction sets were prepared a priori from available experimental datasets in terms of structure and response. These sets were used to derive statistically robust and predictive (both internally and externally) models. The structural applicability domain (AD) of the models were verified on 376 per- and polyfluorinated chemicals including those in REACH preregistration list. The rat and mouse endpoints were predicted by each model for the studied compounds, and finally 30 compounds, all perfluorinated, were prioritized as most important for experimental toxicity analysis under the project. In addition, cumulative study on compounds within the AD of all four models, including two earlier published models on LC(50) rodent analysis was studied and the cumulative toxicity trend was observed using principal component analysis (PCA). The similarities and the differences observed in terms of descriptors and chemical/mechanistic meaning encoded by descriptors to prioritize the most toxic compounds are highlighted.

  10. A tailored mouse model of CLN2 disease: A nonsense mutant for testing personalized therapies.

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    Geraets, Ryan D; Langin, Logan M; Cain, Jacob T; Parker, Camille M; Beraldi, Rosanna; Kovacs, Attila D; Weimer, Jill M; Pearce, David A

    2017-01-01

    The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. The NCLs result in premature death due to the absence of curative therapies. Nevertheless, preclinical and clinical trials exist for various therapies. However, the genotypes of NCL animal models determine which therapeutic approaches can be assessed. Mutations of the CLN2 gene encoding a soluble lysosomal enzyme, tripeptidyl peptidase 1 (TPP1), cause late infantile NCL/CLN2 disease. The genotype of the original mouse model of CLN2 disease, Cln2-/-, excludes mutation guided therapies like antisense oligonucleotides and nonsense suppression. Therefore, the purpose of this study was to develop a model of CLN2 disease that allows for the assessment of all therapeutic approaches. Nonsense mutations in CLN2 disease are frequent, the most common being CLN2R208X. Thus, we created a mouse model that carries a mutation equivalent to the human p.R208X mutation. Molecular assessment of Cln2R207X/R207X tissues determined significant reduction in Cln2 transcript abundance and TPP1 enzyme activity. This reduction leads to the development of neurological impairment (e.g. tremors) and neuropathology (e.g. astrocytosis). Collectively, these assessments indicate that the Cln2R207X/R207X mouse is a valid CLN2 disease model which can be used for the preclinical evaluation of all therapeutic approaches including mutation guided therapies.

  11. New mouse model for inducing and evaluating unilateral vestibular deafferentation syndrome.

    Science.gov (United States)

    Cassel, R; Bordiga, P; Pericat, D; Hautefort, C; Tighilet, B; Chabbert, C

    2018-01-01

    Unilateral vestibular deafferentation syndrome (uVDS) holds a particular place in the vestibular pathology domain. Due to its suddenness, the violence of its symptoms that often result in emergency hospitalization, and its associated original neurophysiological properties, this syndrome is a major source of questioning for the otoneurology community. Also, its putative pathogenic causes remain to be determined. There is currently a strong medical need for the development of targeted and effective countermeasures to improve the therapeutic management of uVDS. The present study reports the development of a new mouse model for inducing and evaluating uVDS. Both the method for generating controlled excitotoxic-type peripheral vestibular damages, through transtympanic administration of the glutamate receptors agonist kainate (TTK), and the procedure for evaluating the ensuing clinical signs are detailed. Through extensive analysis of the clinical symptoms characteristics, this new animal model provides the opportunity to better follow the temporal evolution of various uVDS specific symptoms, while better appreciating the different phases that composed this syndrome. The uVDS evoked in the TTK mouse model displays two main phases distinguishable by their kinetics and amplitudes. Several parameters of the altered vestibular behaviour mimic those observed in the human syndrome. This new murine model brings concrete information about how uVDS develops and how it affects global behaviour. In addition, it opens new opportunity to decipher the etiopathological substrate of this pathology by authorizing the use of genetically modified mouse models. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders.

    Science.gov (United States)

    Burket, Jessica A; Benson, Andrew D; Tang, Amy H; Deutsch, Stephen I

    2014-01-01

    Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behavior, cognition, and neuropathology. However, since only a minority of ASDs are due to the effects of single genes (∼10%), there is a need to explore inhibition of mTOR activity in mouse models that may be more relevant to the majority of nonsyndromic presentations, such as the genetically inbred BTBR T(+)Itpr3(tf)/J (BTBR) mouse model of ASDs. BTBR mice have social impairment and exhibit increased stereotypic behavior. In prior work, d-cycloserine, a partial glycineB site agonist that targets the N-methyl-d-aspartate (NMDA) receptor, was shown to improve sociability in both Balb/c and BTBR mouse models of ASDs. Importantly, NMDA receptor activation regulates mTOR signaling activity. The current study investigated the ability of rapamycin (10mg/kg, i.p.×four days), an mTORC1 inhibitor, to improve sociability and stereotypic behavior in BTBR mice. Using a standard paradigm to assess mouse social behavior, rapamycin improved several measures of sociability in the BTBR mouse, suggesting that mTOR overactivation represents a therapeutic target that mediates or contributes to impaired sociability in the BTBR mouse model of ASDs. Interestingly, there was no effect of rapamycin on stereotypic behaviors in this mouse model. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Application of functional genomics to the chimeric mouse model of HCV infection: optimization of microarray protocols and genomics analysis

    Directory of Open Access Journals (Sweden)

    Smith Maria W

    2006-05-01

    Full Text Available Abstract Background Many model systems of human viral disease involve human-mouse chimeric tissue. One such system is the recently developed SCID-beige/Alb-uPA mouse model of hepatitis C virus (HCV infection which involves a human-mouse chimeric liver. The use of functional genomics to study HCV infection in these chimeric tissues is complicated by the potential cross-hybridization of mouse mRNA on human oligonucleotide microarrays. To identify genes affected by mouse liver mRNA hybridization, mRNA from identical human liver samples labeled with either Cy3 or Cy5 was compared in the presence and absence of known amounts of mouse liver mRNA labeled in only one dye. Results The results indicate that hybridization of mouse mRNA to the corresponding human gene probe on Agilent Human 22 K oligonucleotide microarray does occur. The number of genes affected by such cross-hybridization was subsequently reduced to approximately 300 genes both by increasing the hybridization temperature and using liver samples which contain at least 80% human tissue. In addition, Real Time quantitative RT-PCR using human specific probes was shown to be a valid method to verify the expression level in human cells of known cross-hybridizing genes. Conclusion The identification of genes affected by cross-hybridization of mouse liver RNA on human oligonucleotide microarrays makes it feasible to use functional genomics approaches to study the chimeric SCID-beige/Alb-uPA mouse model of HCV infection. This approach used to study cross-species hybridization on oligonucleotide microarrays can be adapted to other chimeric systems of viral disease to facilitate selective analysis of human gene expression.

  14. Multimodal Genetic Approach for Molecular Imaging of Vasculature in a Mouse Model of Melanoma.

    Science.gov (United States)

    Suero-Abreu, Giselle A; Aristizábal, Orlando; Bartelle, Benjamin B; Volkova, Eugenia; Rodríguez, Joe J; Turnbull, Daniel H

    2017-04-01

    In this study, we evaluated a genetic approach for in vivo multimodal molecular imaging of vasculature in a mouse model of melanoma. We used a novel transgenic mouse, Ts-Biotag, that genetically biotinylates vascular endothelial cells. After inoculating these mice with B16 melanoma cells, we selectively targeted endothelial cells with (strept)avidinated contrast agents to achieve multimodal contrast enhancement of Tie2-expressing blood vessels during tumor progression. This genetic targeting system provided selective labeling of tumor vasculature and showed in vivo binding of avidinated probes with high specificity and sensitivity using microscopy, near infrared, ultrasound, and magnetic resonance imaging. We further demonstrated the feasibility of conducting longitudinal three-dimensional (3D) targeted imaging studies to dynamically assess changes in vascular Tie2 from early to advanced tumor stages. Our results validated the Ts-Biotag mouse as a multimodal targeted imaging system with the potential to provide spatio-temporal information about dynamic changes in vasculature during tumor progression.

  15. Protective Effect of Carvacrol against Gut Dysbiosis and Clostridium difficile Associated Disease in a Mouse Model

    Science.gov (United States)

    Mooyottu, Shankumar; Flock, Genevieve; Upadhyay, Abhinav; Upadhyaya, Indu; Maas, Kendra; Venkitanarayanan, Kumar

    2017-01-01

    This study investigated the effect of carvacrol (CR), a phytophenolic compound on antibiotic-associated gut dysbiosis and C. difficile infection in a mouse model. Five to six-week-old C57BL/6 mice were randomly divided into seven treatment groups (challenge and control) of eight mice each. Mice were fed with irradiated feed supplemented with CR (0, 0.05, and 0.1%); the challenge groups were made susceptible to C. difficile by orally administering an antibiotic cocktail in water and an intra-peritoneal injection of clindamycin. Both challenge and control groups were infected with 105CFU/ml of hypervirulent C. difficile (ATCC 1870) spores or PBS, and observed for clinical signs for 10 days. Respective control groups for CR, antibiotics, and their combination were included for investigating their effect on mouse enteric microflora. Mouse body weight and clinical and diarrhea scores were recorded daily post infection. Fecal samples were collected for microbiome analysis using rRNA sequencing in MiSeq platform. Carvacrol supplementation significantly reduced the incidence of diarrhea and improved the clinical and diarrhea scores in mice (p CR supplementation positively altered the microbiome composition, as revealed by an increased abundance of beneficial bacteria, including Firmicutes, and significantly reduced the proportion of detrimental flora such as Proteobacteria, without significantly affecting the gut microbiome diversity compared to control. Results suggest that CR could potentially be used to control gut dysbiosis and reduce C. difficile infection. PMID:28484429

  16. Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Murphy, Stephanie R; Chang, Catherine Cy; Dogbevia, Godwin; Bryleva, Elena Y; Bowen, Zachary; Hasan, Mazahir T; Chang, Ta-Yuan

    2013-08-01

    Both genetic inactivation and pharmacological inhibition of the cholesteryl ester synthetic enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1) have shown benefit in mouse models of Alzheimer's disease (AD). In this study, we aimed to test the potential therapeutic applications of adeno-associated virus (AAV)-mediated Acat1 gene knockdown in AD mice. We constructed recombinant AAVs expressing artificial microRNA (miRNA) sequences, which targeted Acat1 for knockdown. We demonstrated that our AAVs could infect cultured mouse neurons and glia and effectively knockdown ACAT activity in vitro. We next delivered the AAVs to mouse brains neurosurgically, and demonstrated that Acat1-targeting AAVs could express viral proteins and effectively diminish ACAT activity in vivo, without inducing appreciable inflammation. We delivered the AAVs to the brains of 10-month-old AD mice and analyzed the effects on the AD phenotype at 12 months of age. Acat1-targeting AAV delivered to the brains of AD mice decreased the levels of brain amyloid-β and full-length human amyloid precursor protein (hAPP), to levels similar to complete genetic ablation of Acat1. This study provides support for the potential therapeutic use of Acat1 knockdown gene therapy in AD.

  17. Synergistic effect of lidocaine with pingyangmycin for treatment of venous malformation using a mouse spleen model

    Science.gov (United States)

    Bai, Nan; Chen, Yuan-Zheng; Mao, Kai-Ping; Fu, Yanjie; Lin, Qiang; Xue, Yan

    2014-01-01

    Aims: To explore whether lidocaine has the synergistic effect with pingyangmycin (PYM) in the venous malformations (VMs) treatment. Methods: The mouse spleen was chosen as a VM model and injected with different concentration of lidocaine or PYM or jointly treated with lidocaine and PYM. After 2, 5, 8 or 14 days, the mouse spleen tissues were acquired for hematoxylin-eosin (HE) staining, transmission electron microscopy (TEM) analysis, TUNEL assay and quantitative RT-PCR analysis to examine the toxicological effects of lidocaine and PYM on splenic vascular endothelial cells. Results: 0.4% of lidocaine mildly promoted the apoptosis of endothelial cells, while 2 mg/ml PYM significantly elevated the apoptotic ratios. However, the combination of 0.2% lidocaine and 0.5 mg/ml PYM notably elevated the apoptotic ratios of splenic cells and severely destroyed the configuration of spleen, compared to those of treatment with 0.5 mg/ml PYM alone. Conclusion: Lidocaine exerts synergistic effects with PYM in promoting the apoptosis of mouse splenic endothelial cells, indicating that lidocaine possibly promotes the therapeutic effects of PYM in VMs treatment via synergistically enhancing the apoptosis of endothelial cells of malformed venous lesions. PMID:24966943

  18. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism.

    Science.gov (United States)

    Shroff, Emelyn H; Eberlin, Livia S; Dang, Vanessa M; Gouw, Arvin M; Gabay, Meital; Adam, Stacey J; Bellovin, David I; Tran, Phuoc T; Philbrick, William M; Garcia-Ocana, Adolfo; Casey, Stephanie C; Li, Yulin; Dang, Chi V; Zare, Richard N; Felsher, Dean W

    2015-05-26

    The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.

  19. Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC of the infraorbital nerve

    Directory of Open Access Journals (Sweden)

    Ma Fei

    2012-12-01

    Full Text Available Abstract Background Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity. Results The chronic orofacial neuropathic pain model is induced after surgical placement of chromic gut suture in the infraorbital nerve fissure in the maxillary bone. Slight compression and chemical effects of the chromic gut suture on the portion of the infraorbital nerve contacted cause mild nerve trauma. Nerve edema is observed in the contacting infraorbital nerve bundle as well as macrophage infiltration in the trigeminal ganglia. Centrally in the spinal trigeminal nucleus, increased immunoreactivity for an activated microglial marker is evident (OX42, postoperative day 70. Mechanical thresholds of the affected whisker pad are significantly decreased on day 3 after chromic gut suture placement, persisting at least 10 weeks. The mechanical allodynia is reversed by suppression of microglial activation. Cold allodynia was detected at 4 weeks. Conclusions A simple, effective, and reproducible chronic mouse model mimicking clinical orofacial neuropathic pain (Type 2 is induced by placing chromic gut suture between the infraorbital nerve and the maxillary bone. The method produces mild inflammatory compression with significant continuous mechanical allodynia persisting at least 10 weeks and cold allodynia measureable at 4 weeks.

  20. A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis.

    Science.gov (United States)

    Bornfeldt, Karin E; Kramer, Farah; Batorsky, Anna; Choi, Jinkuk; Hudkins, Kelly L; Tontonoz, Peter; Alpers, Charles E; Kanter, Jenny E

    2017-11-15

    Diabetic kidney disease and atherosclerotic disease are major causes of morbidity and mortality associated with type 2 diabetes (T2D), and diabetic kidney disease is a major cardiovascular risk factor. The BTBR mouse strain with leptin-deficiency (Lepob) has emerged as one of the best models of human diabetic kidney disease. However, no T2D mouse model of combined diabetic kidney disease and atherosclerosis exists. Our goal was to generate such a model. To this end, the LDL receptor was targeted for degradation via IDOL (inducible degrader of the LDL receptor) overexpression, using a liver-targeted adeno-associated virus (AAV-DJ/8) in BTBR wild-type (WT) and BTBR Lepob (OB) mice. Liver-targeted IDOL-AAV-DJ/8 increased plasma LDL cholesterol, as compared with the control eGFP-AAV-DJ/8. IDOL-induced dyslipidemia caused formation of atherosclerotic lesions of an intermediate stage, which contained both macrophages and smooth muscle cells. BTBR OB mice exhibited diabetic kidney disease. IDOL-induced dyslipidemia worsened albuminuria and glomerular macrophage accumulation, but had no effect on mesangial expansion or podocyte numbers. Thus, by inducing hepatic degradation of the LDL receptor, we generated a T2D model of combined kidney disease and atherosclerosis. This model provides a new tool to study mechanisms, interactions, and treatment strategies of kidney disease and atherosclerosis in T2D. Copyright © 2017. Published by Elsevier Inc.

  1. A Biokinetic Model for Alpha-emitting Bone Surface-seeking Radionuclides in the Mouse Skeleton

    Energy Technology Data Exchange (ETDEWEB)

    Austin, A.L.; Lord, B.I

    2000-07-01

    Following intake of an alpha-emitting bone surface-seeking radionuclide, such as {sup 239}Pu or {sup 241}Am, a major site of retention is the skeleton. Within the skeleton, these radionuclides are initially deposited on the bone surfaces, but subsequently redistributed as a result of the process of bone remodelling. In this study, these processes have been modelled in the mouse femoral shaft, by development of a multicompartmental biokinetic model. The model consists of bone surface, volume and marrow and blood compartments, each of which are described by input parameters. The majority of parameter values were obtained from current literature, and the remainder obtained by fitting of the model to microdistribution and radiation dosimetry data taken from previous autoradiographical analyses of the mouse femoral shaft, at times from 1 to 448 days after a 40 kBq.kg{sup -1} injection of either {sup 239}Pu or {sup 241}Am. Results of fitting the model to these data predict that (a) {sup 239}Pu and {sup 241}Am show equal affinities for both resorbing and forming bone surfaces, (b) {sup 241}Am is retained in macrophages for a longer period than {sup 239}Pu and, (c) the cumulative dose to the region of marrow containing the osteosarcomagenic target cells is higher for {sup 239}Pu than {sup 241}Am by a factor of two. (author)

  2. Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research

    Science.gov (United States)

    Rai, Vikrant; Sharma, Poonam; Agrawal, Swati

    2016-01-01

    Heart disease causing cardiac cell death due to ischemia–reperfusion injury is a major cause of morbidity and mortality in the United States. Coronary heart disease and cardiomyopathies are the major cause for congestive heart failure, and thrombosis of the coronary arteries is the most common cause of myocardial infarction. Cardiac injury is followed by post-injury cardiac remodeling or fibrosis. Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac inter-stitium and results in both systolic and diastolic dysfunctions. It has been suggested by both experimental and clinical evidence that fibrotic changes in the heart are reversible. Hence, it is vital to understand the mechanism involved in the initiation, progression, and resolution of cardiac fibrosis to design anti-fibrotic treatment modalities. Animal models are of great importance for cardiovascular research studies. With the developing research field, the choice of selecting an animal model for the proposed research study is crucial for its outcome and translational purpose. Compared to large animal models for cardiac research, the mouse model is preferred by many investigators because of genetic manipulations and easier handling. This critical review is focused to provide insight to young researchers about the various mouse models, advantages and disadvantages, and their use in research pertaining to cardiac fibrosis and hypertrophy. PMID:27766529

  3. Original Research: Different imiquimod creams resulting in differential effects for imiquimod-induced psoriatic mouse models.

    Science.gov (United States)

    Luo, Di-Qing; Wu, Hui-Hui; Zhao, Yu-Kun; Liu, Juan-Hua; Wang, Fang

    2016-10-01

    Imiquimod (IMQ)-induced mouse psoriatic model is one of the useful models displaying most of psoriatic features. To compare the modeling efficacy of different IMQ creams, we induced the psoriatic models by topically applying two different brands of IMQ 5% creams to the shaved Balb/c mice skin and assessed the results. Balb/c female mice (n = 24) 8-12 weeks of age were randomly divided into experimental groups A (Likejie), B (Aldara), and control group C (Vaseline); Likejie, Aldara, or Vaseline was topically applied to the back skin for mice in groups A, B, and C, respectively, for six consecutive days. The total psoriasis area and severity index scores of groups A, B, and C were 3.25 ± 1.56, 9.81 ± 0.84, and 0, respectively; the Baker's scores were 2.93 ± 1.07, 6.47 ± 1.50, and 0, respectively; and the epidermis thickness was 49.79 ± 14.16, 85.62 ± 17.55, and 20.04 ± 3.68 µm, respectively. The differences between the three groups in dual were statistically significant (P creams may result in differential efficacy when performing the IMQ-induced psoriasis mouse models. © 2016 by the Society for Experimental Biology and Medicine.

  4. No evidence of non-homologous insertions in mouse model of MDD created by replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence.

    Science.gov (United States)

    Zubenko, George S; Hughes, Hugh B

    2012-01-01

    We have recently reported the creation and initial characterization of the first etiology-based recombinant mouse model of major depressive disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with the development of MDD in families identified by probands with recurrent, early-onset MDD. The current study explored whether the desired homologous recombination event at the mouse Creb1 gene that resulted in the creation of the mouse model was also accompanied by insertions of the targeting vector at unintended non-homologous locations in the mouse genome. No evidence of insertions of targeting vector sequence was observed at regions other than the mouse Creb1 gene. Copyright © 2011 Wiley Periodicals, Inc.

  5. Effects of oxidative stress on hyperglycaemia-induced brain malformations in a diabetes mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Ya [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China); Wang, Guang [Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632 (China); Han, Sha-Sha; He, Mei-Yao [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China); Cheng, Xin; Ma, Zheng-Lai [Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632 (China); Wu, Xia [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China); Yang, Xuesong, E-mail: yang_xuesong@126.com [Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632 (China); Liu, Guo-Sheng, E-mail: tlgs@jnu.edu.cn [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China)

    2016-09-10

    Pregestational diabetes mellitus (PGDM) enhances the risk of fetal neurodevelopmental defects. However, the mechanism of hyperglycaemia-induced neurodevelopmental defects is not fully understood. In this study, several typical neurodevelopmental defects were identified in the streptozotocin-induced diabetes mouse model. The neuron-specific class III beta-tubulin/forkhead box P1-labelled neuronal differentiation was suppressed and glial fibrillary acidic protein-labelled glial cell lineage differentiation was slightly promoted in pregestational diabetes mellitus (PGDM) mice. Various concentrations of glucose did not change the U87 cell viability, but glial cell line-derived neurotrophic factor expression was altered with varying glucose concentrations. Mouse maternal hyperglycaemia significantly increased Tunel{sup +} apoptosis but did not dramatically affect PCNA{sup +} cell proliferation in the process. To determine the cause of increased apoptosis, we determined the SOD activity, the expression of Nrf2 as well as its downstream anti-oxidative factors NQO1 and HO1, and found that all of them significantly increased in PGDM fetal brains compared with controls. However, Nrf2 expression in U87 cells was not significantly changed by different glucose concentrations. In mouse telencephalon, we observed the co-localization of Tuj-1 and Nrf2 expression in neurons, and down-regulating of Nrf2 in SH-SY5Y cells altered the viability of SH-SY5Y cells exposed to high glucose concentrations. Taken together, the data suggest that Nrf2-modulated antioxidant stress plays a crucial role in maternal hyperglycaemia-induced neurodevelopmental defects. - Highlights: • Typical neurodevelopmental defects could be observed in STZ-treated mouse fetuses. • Nrf2 played a crucial role in hyperglycaemia-induced brain malformations. • The effects of hyperglycaemia on neurons and glia cells were not same.

  6. Dynamic gene expression analysis in a H1N1 influenza virus mouse pneumonia model.

    Science.gov (United States)

    Bao, Yanyan; Gao, Yingjie; Shi, Yujing; Cui, Xiaolan

    2017-06-01

    H1N1, a major pathogenic subtype of influenza A virus, causes a respiratory infection in humans and livestock that can range from a mild infection to more severe pneumonia associated with acute respiratory distress syndrome. Understanding the dynamic changes in the genome and the related functional changes induced by H1N1 influenza virus infection is essential to elucidating the pathogenesis of this virus and thereby determining strategies to prevent future outbreaks. In this study, we filtered the significantly expressed genes in mouse pneumonia using mRNA microarray analysis. Using STC analysis, seven significant gene clusters were revealed, and using STC-GO analysis, we explored the significant functions of these seven gene clusters. The results revealed GOs related to H1N1 virus-induced inflammatory and immune functions, including innate immune response, inflammatory response, specific immune response, and cellular response to interferon-beta. Furthermore, the dynamic regulation relationships of the key genes in mouse pneumonia were revealed by dynamic gene network analysis, and the most important genes were filtered, including Dhx58, Cxcl10, Cxcl11, Zbp1, Ifit1, Ifih1, Trim25, Mx2, Oas2, Cd274, Irgm1, and Irf7. These results suggested that during mouse pneumonia, changes in the expression of gene clusters and the complex interactions among genes lead to significant changes in function. Dynamic gene expression analysis revealed key genes that performed important functions. These results are a prelude to advancements in mouse H1N1 influenza virus infection biology, as well as the use of mice as a model organism for human H1N1 influenza virus infection studies.

  7. [Establishment of Humanized Mouse Model by Using Transplantation of Mobilized Peripheral Blood Stem Cells].

    Science.gov (United States)

    Xu, Ya-Ru; Li, Yu-Hang; Chen, Shui-Ping; Zou, Bing-Han; Zhang, Qin; Xu, Man; Kong, Wei-Xia; Sheng, Hong-Xia; Hu, Guo-Liang; Liao, Li; Zhang, Bin; Hu, Liang-Ding

    2015-12-01

    To investigate the hematopoietic reconstitution in immunodeficiency NPG(TM) mice after transplantation of G-CSF-mobilized peripheral blood CD34(+) hemopoietic stem cells. CD34(+) cells were isolated from peripheral blood stem cells (PBSC) by magnetic activated cell sorting (MACS), and then were transplanted into NPG(TM) mice irradiated with sublethal dose of X ray by marrow cavity transplantation. The hemogram of mice after transplantation for 2, 4 weeks was observed; human cell populations (CD45(+), CD19(+)) in the peripheral blood of mice were dynamically analyzed by flow cytometry (FCM) at 4, 6, 8, 10 and 12 weeks after transplantation. Until the planned harvest at the 12 week after transplantation, the CD45(+), CD19(+) level in bone marrow, liver, spleen from each mouse were detected by flow cytometry; the expression of human Alu gene in the bone marrow cell of mouse was detected by PCR. The purity of CD34(+) cells accounted for 96.3%; after irradiation, the nucleated cells and megalokaryocytes in the marrow cavity of NPG mice were reduced significantly or were lost, and reached the myeloablative effect. At week 4 after transplantation, components of blood cells in peripheral blood of transplanted mice were recovered to the level before irradiation; all the mice survived, human CD45(+), CD19(+) cells were found by FCM in the peripheral blood of all the surviving mice in transplantation group at week 4, 6, 8, 10, 12 after the transplantation; at the 12th week, the human Alu gene could be detected in the bone marrow of all the mice in transplantation group. The human-mouse chimeric model is successfully established in irradiation-induced NPG mouse by transplantation of CD34(+) HSC from G-CSF-mobilized peripheral blood via marrow cavity.

  8. Development of a mouse model of abdominal cutaneous flaps for breast reconstruction.

    Directory of Open Access Journals (Sweden)

    Daniel John Womac

    Full Text Available UNLABELLED: Autologous tissue transfer, in addition to replacing tissue that was lost during injury or surgery, offers women an excellent option to improve cosmetic appearance and self-confidence following mastectomy due to breast cancer. However, flap necrosis is a complication in obese patients undergoing this procedure. We created a mouse model to study the flap-related complications that leads to decreased flap survival in autologous breast reconstruction. METHODS: Left superficial inferior epigastric (SIE pedicle abdominal-cutaneous flaps were elevated in 8 week-old, obese ob/ob male mice and their lean littermates. Flaps were followed by serial photography. Area of flap necrosis was measured at 7 days. Statistical analysis was performed. RESULTS: Necrosis was observed at the distal margin of the flaps, in both lean and obese groups. Lean left SIE flaps (n = 8 had a total area flap necrosis of 9.1% at 7 days whereas obese left SIE flaps (n = 8 had a total area flap necrosis of 45.5% at 7 days. Obese flaps had a statistically significant increase in necrosis compared to the lean flaps, p = 0.001. CONCLUSIONS: There was a significant difference between flap survival in lean and obese SIE pedicle flaps in our mouse model. We have developed the first flap model of obesity utilizing the superficial epigastric pedicle in the mouse. This model is optimal for future studies to dissect out mechanisms that lead to the complications related to flap survival for breast reconstruction, especially in obese subjects.

  9. Dysbiosis of the fecal microbiota in the TNBS-induced Crohn's disease mouse model.

    Science.gov (United States)

    He, Qing; Li, Xiaoping; Liu, Chuan; Su, Lili; Xia, Zhongkui; Li, Xin; Li, Ying; Li, Lingling; Yan, Ting; Feng, Qiang; Xiao, Liang

    2016-05-01

    Crohn's disease (CD) is characterized by chronic transmural inflammation. The symptom of the mice model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) is closed to human under CD condition, so this kind of animal is widely used in the related researches. Although the dysbiosis of the fecal microbiota has been proved to play an important role in the patients with CD, the composition of the gastrointestinal microbiota in the mouse model under disease condition is still unclear. In the current study, male 7-week BALB/c mice were anesthetized and intrarectal administrated by ethanol (ET group), TNBS in ethanol (TN group), and phosphate buffered saline (PBS) (CK group) as control. The symptoms of individuals under the CD condition were observed, and the changes of the bacterial taxonomic structure and functional composition were revealed by next-generation sequencing (NGS) 16S sequencing. The BALB/c mice in TN group demonstrated CD-like symptoms and the damages in the intestinal tract. The NGS 16S results exhibited that the diversity and microbial composition under CD condition are significantly different with those in ET group. The KEGG Orthology (KO) profile were generated from PICRUSt, and function modules such as methanogenesis (M00347) and microcin C transport system (M00349) were found enriched in the individuals in the TN group. This study proved that mouse model induced by TNBS could develop the similar symptom to CD patient, and we firstly showed the significant intestinal microbe changes on both taxonomic structure and functional composition in this mouse model.

  10. Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.

    Science.gov (United States)

    Siegmund, Stephanie E; Yang, Hua; Sharma, Rohit; Javors, Martin; Skinner, Owen; Mootha, Vamsi; Hirano, Michio; Schon, Eric A

    2017-12-01

    Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism. Here, we administered low-dose oral rapamycin to a knock-in (KI) mouse model of authentic mtDNA disease, specifically, progressive mtDNA depletion syndrome, resulting from a mutation in the mitochondrial nucleotide salvage enzyme thymidine kinase 2 (TK2). Importantly, low-dose oral rapamycin was sufficient to extend Tk2KI/KI mouse lifespan significantly, and did so in the absence of detectable improvements in mitochondrial dysfunction. We found no evidence that rapamycin increased survival by acting through canonical pathways, including mitochondrial autophagy. However, transcriptomics and metabolomics analyses uncovered systemic metabolic changes pointing to a potential 'rapamycin metabolic signature.' These changes also implied that rapamycin may have enabled the Tk2KI/KI mice to utilize alternative energy reserves, and possibly triggered indirect signaling events that modified mortality through developmental reprogramming. From a therapeutic standpoint, our results support the possibility that low-dose rapamycin, while not targeting the underlying mtDNA defect, could represent a crucial therapy for the treatment of mtDNA-driven, and some nuclear DNA-driven, mitochondrial diseases. © The Author 2017. Published by Oxford University Press.

  11. Inner ear morphology is perturbed in two novel mouse models of recessive deafness.

    Directory of Open Access Journals (Sweden)

    Kerry A Miller

    Full Text Available Human MYO7A mutations can cause a variety of conditions involving the inner ear. These include dominant and recessive non-syndromic hearing loss and syndromic conditions such as Usher syndrome. Mouse models of deafness allow us to investigate functional pathways involved in normal and abnormal hearing processes. We present two novel mouse models with mutations in the Myo7a gene with distinct phenotypes. The mutation in Myo7a(I487N/I487N ewaso is located within the head motor domain of Myo7a. Mice exhibit a profound hearing loss and manifest behaviour associated with a vestibular defect. A mutation located in the linker region between the coiled-coil and the first MyTH4 domains of the protein is responsible in Myo7a(F947I/F947I dumbo. These mice show a less severe hearing loss than in Myo7a(I487N/I487N ewaso; their hearing loss threshold is elevated at 4 weeks old, and progressively worsens with age. These mice show no obvious signs of vestibular dysfunction, although scanning electron microscopy reveals a mild phenotype in vestibular stereocilia bundles. The Myo7a(F947I/F947I dumbo strain is therefore the first reported Myo7a mouse model without an overt vestibular phenotype; a possible model for human DFNB2 deafness. Understanding the molecular basis of these newly identified mutations will provide knowledge into the complex genetic pathways involved in the maintenance of hearing, and will provide insight into recessively inherited sensorineural hearing loss in humans.

  12. Maternal separation with early weaning: a novel mouse model of early life neglect

    Directory of Open Access Journals (Sweden)

    Elwafi Hani M

    2010-09-01

    Full Text Available Abstract Background Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse. Results In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW. We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect. Conclusions These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.

  13. Maternal separation with early weaning: a novel mouse model of early life neglect.

    Science.gov (United States)

    George, Elizabeth D; Bordner, Kelly A; Elwafi, Hani M; Simen, Arthur A

    2010-09-29

    Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse. In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW). We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test) when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect. These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.

  14. Optimization and Standardization of the Immunodeficient Mouse Model for Assessing Fat Grafting Outcomes.

    Science.gov (United States)

    Kokai, Lauren E; Jones, Taraneh L; Silowash, Russell; Theisen, Brian; DiBernardo, Gabriella; Lu, Andrew; Yi, Bowen; Marra, Kacey G; Rubin, J Peter

    2017-12-01

    Animal models are often used to assess interventions that might improve fat grafting outcomes; however, there is great variability in the models. The authors sought to determine the predictive value of the immunocompromised mouse model for fat grafting so that experiments could be standardized and optimized. Human lipoaspirate injections at different volumes and time points were assessed in a nude mouse model and compared with control injections of nonviable fat. Volume retention and explant histologic score were compared. In a separate study, interanimal reproducibility was determined by implanting a highly consistent hydrogel and measuring variability in volume retention. Injection volume significantly affects adipose resorption kinetics at 6 and 12 weeks. Masson trichrome staining revealed that macrophages were unable to infiltrate large (1 ml) grafts, and oil cysts were not absorbed by 18 weeks, which interfered with interpretation of volume retention data. Nonviable tissue was resorbed when grafts were 0.3 ml, and quantification of graft histologic viability correlated well with graft retention at all study time points. Interanimal variability was measured to be 8.44 percent of the mean retention volume for small graft volumes. Human fat graft retention in the immunodeficient mouse correlates with graft viability in small, 0.3-ml-volume grafts. However, centralized oil cysts in nonviable 1.0-ml grafts were not resorbed by 18 weeks and thus volume measurements were confounded and not significantly different from viable samples. In addition, tissue injury scores increased in initially healthy fat grafts at 18 weeks, possibly because of a delayed immune reaction.

  15. Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta.

    Science.gov (United States)

    Roschger, Andreas; Roschger, Paul; Keplingter, Petra; Klaushofer, Klaus; Abdullah, Sami; Kneissel, Michaela; Rauch, Frank

    2014-09-01

    Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1(Jrt)/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

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    James N. Sleigh

    2011-07-01

    Full Text Available Spinal muscular atrophy (SMA, which is caused by inactivating mutations in the survival motor neuron 1 (SMN1 gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS, requires further exploration.

  17. Follistatin is a metastasis suppressor in a mouse model of HER2-positive breast cancer.

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    Seachrist, Darcie D; Sizemore, Steven T; Johnson, Emhonta; Abdul-Karim, Fadi W; Weber Bonk, Kristen L; Keri, Ruth A

    2017-06-05

    Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-β superfamily of ligands. The prognostic value of FST and its family members, the follistatin-like (FSTL) proteins, have been studied in various cancers. However, these studies, as well as limited functional analyses of the FSTL proteins, have yielded conflicting results on the role of these proteins in disease progression. Furthermore, very few have been focused on FST itself. We assessed whether FST may be a suppressor of tumorigenesis and/or metastatic progression in breast cancer. Using publicly available gene expression data, we examined the expression patterns of FST and INHBA, a subunit of activin, in normal and cancerous breast tissue and the prognostic value of FST in breast cancer metastases, recurrence-free survival, and overall survival. The functional effects of activin and FST on in vitro proliferation, migration, and invasion of breast cancer cells were also examined. FST overexpression in an autochthonous mouse model of breast cancer was then used to assess the in vivo impact of FST on metastatic progression. Examination of multiple breast cancer datasets revealed that FST expression is reduced in breast cancers compared with normal tissue and that low FST expression predicts increased metastasis and reduced overall survival. FST expression was also reduced in a mouse model of HER2/Neu-induced metastatic breast cancer. We found that FST blocks activin-induced breast epithelial cell migration in vitro, suggesting that its loss may promote breast cancer aggressiveness. To directly determine if FST restoration could inhibit metastatic progression, we transgenically expressed FST in the HER2/Neu model. Although FST had no impact on tumor initiation or growth, it completely blocked the formation of lung metastases. These data indicate that FST is a bona fide metastasis suppressor in this mouse model and support future efforts to develop an FST mimetic to

  18. CINcere Modelling : What Have Mouse Models for Chromosome Instability Taught Us?

    NARCIS (Netherlands)

    Simon, Judith E; Bakker, Bjorn; Foijer, Floris

    2015-01-01

    Chromosomal instability (CIN) is a process leading to errors in chromosome segregation and results in aneuploidy, a state in which cells have an abnormal number of chromosomes. CIN is a hallmark of cancer, and furthermore linked to ageing and age-related diseases such as Alzheimer's. Various mouse

  19. Centralized mouse repositories.

    Science.gov (United States)

    Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

    2012-10-01

    Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

  20. Evaluation of TorsinA as a target for Parkinson disease therapy in mouse models.

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    Li, Xinru; Lee, Jenny; Parsons, Dee; Janaurajs, Karen; Standaert, David G

    2012-01-01

    Parkinson disease (PD) is a common and disabling disorder. No current therapy can slow or reverse disease progression. An important aspect of research in this field is target validation, a systematic approach to evaluating the likelihood that modification of a certain molecule, mechanism or biological pathway may be useful for the development of pharmacological or molecular treatments for the disease. TorsinA, a member of the AAA+ family of chaperone proteins, has been proposed as a potential target of neuroprotective therapy. TorsinA is found in Lewy bodies in human PD, and can suppress toxicity in cellular and invertebrate models of PD. Here, we evaluated the neuroprotective properties of torsinA in mouse models of PD based on intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as recombinant adeno associated virus (rAAV) induced overexpression of alpha-synuclein (α-syn). Using either transgenic mice with overexpression of human torsinA (hWT mice) or mice in which torsinA expression was induced using an rAAV vector, we found no evidence for protection against acute MPTP intoxication. Similarly, genetic deletion of the endogenous mouse gene for torsinA (Dyt1) using an rAAV delivered Cre recombinase did not enhance the vulnerability of dopaminergic neurons to MPTP. Overexpression of α-syn using rAAV in the mouse substantia nigra lead to a loss of TH positive neurons six months after administration, and no difference in the degree of loss was observed between transgenic animals expressing forms of torsinA and wild type controls. Collectively, we did not observe evidence for a protective effect of torsinA in the mouse models we examined. Each of these models has limitations, and there is no single model with established predictive value with respect to the human disease. Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD.

  1. Evaluation of TorsinA as a target for Parkinson disease therapy in mouse models.

    Directory of Open Access Journals (Sweden)

    Xinru Li

    Full Text Available Parkinson disease (PD is a common and disabling disorder. No current therapy can slow or reverse disease progression. An important aspect of research in this field is target validation, a systematic approach to evaluating the likelihood that modification of a certain molecule, mechanism or biological pathway may be useful for the development of pharmacological or molecular treatments for the disease. TorsinA, a member of the AAA+ family of chaperone proteins, has been proposed as a potential target of neuroprotective therapy. TorsinA is found in Lewy bodies in human PD, and can suppress toxicity in cellular and invertebrate models of PD. Here, we evaluated the neuroprotective properties of torsinA in mouse models of PD based on intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP as well as recombinant adeno associated virus (rAAV induced overexpression of alpha-synuclein (α-syn. Using either transgenic mice with overexpression of human torsinA (hWT mice or mice in which torsinA expression was induced using an rAAV vector, we found no evidence for protection against acute MPTP intoxication. Similarly, genetic deletion of the endogenous mouse gene for torsinA (Dyt1 using an rAAV delivered Cre recombinase did not enhance the vulnerability of dopaminergic neurons to MPTP. Overexpression of α-syn using rAAV in the mouse substantia nigra lead to a loss of TH positive neurons six months after administration, and no difference in the degree of loss was observed between transgenic animals expressing forms of torsinA and wild type controls. Collectively, we did not observe evidence for a protective effect of torsinA in the mouse models we examined. Each of these models has limitations, and there is no single model with established predictive value with respect to the human disease. Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD.

  2. Rabbit and Mouse Models of HSV-1 Latency, Reactivation, and Recurrent Eye Diseases

    Science.gov (United States)

    Webre, Jody M.; Hill, James M.; Nolan, Nicole M.; Clement, Christian; McFerrin, Harris E.; Bhattacharjee, Partha S.; Hsia, Victor; Neumann, Donna M.; Foster, Timothy P.; Lukiw, Walter J.; Thompson, Hilary W.

    2012-01-01

    The exact mechanisms of HSV-1 establishment, maintenance, latency, reactivation, and also the courses of recurrent ocular infections remain a mystery. Comprehensive understanding of the HSV-1 disease process could lead to prevention of HSV-1 acute infection, reactivation, and more effective treatments of recurrent ocular disease. Animal models have been used for over sixty years to investigate our concepts and hypotheses of HSV-1 diseases. In this paper we present descriptions and examples of rabbit and mouse eye models of HSV-1 latency, reactivation, and recurrent diseases. We summarize studies in animal models of spontaneous and induced HSV-1 reactivation and recurrent disease. Numerous stimuli that induce reactivation in mice and rabbits are described, as well as factors that inhibit viral reactivation from latency. The key features, advantages, and disadvantages of the mouse and rabbit models in relation to the study of ocular HSV-1 are discussed. This paper is pertinent but not intended to be all inclusive. We will give examples of key papers that have reported novel discoveries related to the review topics. PMID:23091352

  3. Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model.

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    Daniel Alvarez-Fischer

    Full Text Available Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD. For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a potential protective action of apamin in animal models of PD is available to date. The specific goals of the present study were to (i establish that the protective effect of bee venom for dopaminergic neurons is not restricted to acupoint stimulation, but can also be observed using a more conventional mode of administration and to (ii demonstrate that apamin can mimic the protective effects of a bee venom treatment on dopaminergic neurons. Using the chronic mouse model of MPTP/probenecid, we show that bee venom provides sustained protection in an animal model that mimics the chronic degenerative process of PD. Apamin, however, reproduced these protective effects only partially, suggesting that other components of bee venom enhance the protective action of the peptide.

  4. Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

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    Qifeng Zhou

    2015-01-01

    Full Text Available Mutations in the giant sarcomeric protein titin (TTN are a major cause for inherited forms of dilated cardiomyopathy (DCM. We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygous Ttn knock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC in heterozygous (Het Ttn knock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction (p<0.05, while wild-type (WT TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure.

  5. What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Reevaluating the Potential of Mouse Models for the Human Immune System.

    Science.gov (United States)

    Jameson, Stephen C; Masopust, David

    2017-03-27

    Much of what we understand about immunology, including the response to vaccines, come from studies in mice because they provide many practical advantages compared with research in higher mammals and humans. Nevertheless, modalities for preventing or treating disease do not always translate from mouse to humans, which has led to increasing scrutiny of the continued merits of mouse research. Here, we summarize the pros and cons of current laboratory mouse models for immunology research and discuss whether overreliance on nonphysiological, ultra-hygienic animal husbandry approaches has limited the ultimate translation potential of mouse-derived data to humans. Alternative approaches are discussed that may extend the use of the mouse model for preclinical studies. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  6. Mechanisms of intestinal inflammation and development of associated cancers: Lessons learned from mouse models

    Science.gov (United States)

    Westbrook, Aya M.; Szakmary, Akos; Schiestl, Robert H.

    2010-01-01

    Chronic inflammation is strongly associated with approximately 1/5th of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With regards

  7. Brain accumulation of myo-inositol in the trisomy 16 mouse, an animal model of Down's syndrome.

    OpenAIRE

    Shetty, H U; Holloway, H W; Acevedo, L D; Galdzicki, Z.

    1996-01-01

    myo-Inositol and several other polyols were measured in the tissues of the trisomy 16 mouse (animal model of Down's Syndrome; human trisomy 21) and diploid controls. myo-Inositol was found to be selectively elevated in the brain of the trisomy 16 mouse. However, peripheral tissues showed no elevation. These results are consistent with the cerebrospinal fluid and plasma data reported previously on myo-inositol in Down's Syndrome subjects.

  8. Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism.

    Science.gov (United States)

    Moy, Sheryl S; Riddick, Natallia V; Nikolova, Viktoriya D; Teng, Brian L; Agster, Kara L; Nonneman, Randal J; Young, Nancy B; Baker, Lorinda K; Nadler, Jessica J; Bodfish, James W

    2014-02-01

    Restricted repetitive behaviors are core symptoms of autism spectrum disorders (ASDs). The range of symptoms encompassed by the repetitive behavior domain includes lower-order stereotypy and self-injury, and higher-order indices of circumscribed interests and cognitive rigidity. Heterogeneity in clinical ASD profiles suggests that specific manifestations of repetitive behavior reflect differential neuropathology. The present studies utilized a set of phenotyping tasks to determine a repetitive behavior profile for the C58/J mouse strain, a model of ASD core symptoms. In an observational screen, C58/J demonstrated overt motor stereotypy, but not over-grooming, a commonly-used measure for mouse repetitive behavior. Amphetamine did not exacerbate motor stereotypy, but had enhanced stimulant effects on locomotion and rearing in C58/J, compared to C57BL/6J. Both C58/J and Grin1 knockdown mice, another model of ASD-like behavior, had marked deficits in marble-burying. In a nose poke task for higher-order repetitive behavior, C58/J had reduced holeboard exploration and preference for non-social, versus social, olfactory stimuli, but did not demonstrate cognitive rigidity following familiarization to an appetitive stimulus. Analysis of available high-density genotype data indicated specific regions of divergence between C58/J and two highly-sociable strains with common genetic lineage. Strain genome comparisons identified autism candidate genes, including Cntnap2 and Slc6a4, located within regions divergent in C58/J. However, Grin1, Nlgn1, Sapap3, and Slitrk5, genes linked to repetitive over-grooming, were not in regions of divergence. These studies suggest that specific repetitive phenotypes can be used to distinguish ASD mouse models, with implications for divergent underlying mechanisms for different repetitive behavior profiles. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Antioxidants Halt Axonal Degeneration in a Mouse Model of X-Adrenoleukodystrophy

    Science.gov (United States)

    López-Erauskin, Jone; Fourcade, Stéphane; Galino, Jorge; Ruiz, Montserrat; Schlüter, Agatha; Naudi, Alba; Jove, Mariona; Portero-Otin, Manuel; Pamplona, Reinald; Ferrer, Isidre; Pujol, Aurora

    2011-01-01

    Objective Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD). Methods X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD. Results Here, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests. Interpretation We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor. Ann Neurol 2011; PMID:21786300

  10. Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three-Dimensional Ultrasound Imaging Technique

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    Jie Ni

    2016-02-01

    Full Text Available Prostate cancer (CaP is the most commonly diagnosed and the second leading cause of death from cancer in males in USA. Prostate orthotopic mouse model has been widely used to study human CaP in preclinical settings. Measurement of changes in tumor size obtained from noninvasive diagnostic images is a standard method for monitoring responses to anticancer modalities. This article reports for the first time the usage of a three-dimensional (3D ultrasound system equipped with photoacoustic (PA imaging in monitoring longitudinal prostate tumor growth in a PC-3 orthotopic NODSCID mouse model (n = 8. Two-dimensional and 3D modes of ultrasound show great ability in accurately depicting the size and shape of prostate tumors. PA function on two-dimensional and 3D images showed average oxygen saturation and average hemoglobin concentration of the tumor. Results showed a good fit in representative exponential tumor growth curves (n = 3; r2 = 0.948, 0.955, and 0.953, respectively and a good correlation of tumor volume measurements performed in vivo with autopsy (n = 8, r = 0.95, P < .001. The application of 3D ultrasound imaging proved to be a useful imaging modality in monitoring tumor growth in an orthotopic mouse model, with advantages such as high contrast, uncomplicated protocols, economical equipment, and nonharmfulness to animals. PA mode also enabled display of blood oxygenation surrounding the tumor and tumor vasculature and angiogenesis, making 3D ultrasound imaging an ideal tool for preclinical cancer research.

  11. Depletion of Stercobilin in Fecal Matter from a Mouse Model of Autism Spectrum Disorders

    Science.gov (United States)

    Sekera, Emily R.; Rudolph, Heather L.; Carro, Stephen D.; Morales, Michael J.; Bett, Glenna C. L.; Rasmusson, Randall L.; Wood, Troy D.

    2017-01-01

    Introduction Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders lacking a clinical biomarker for diagnosis. Emerging evidence shows that intestinal microflora from ASD subjects can be distinguished from controls, suggesting metabolite differences due to the action of intestinal microbes may provide a means for identifying potential biomarkers for ASD. Objectives The aim of this study was to determine if quantitative differences in levels of stercobilin and stercobilinogen, metabolites produced by biological action of intestinal microflora, exist in the fecal matter between an ASD mouse model population and controls. Methods Pairs of fecal samples were collected from two mouse groups, an ASD model group with Timothy syndrome 2 (TS2-NEO) and a gender-matched control group. After centrifugation, supernatant was spiked with an 18O-labeled stercobilin isotopomer and subjected to solid phase extraction for processing. Extracted samples were spotted on a stainless steel plate and subjected to matrix-assisted laser desorption and ionization mass spectrometry using dihydroxybenzoic acid as the matrix (n = 5). Peak areas for bilins and 18O-stercobilin isotopomers were determined in each fecal sample. Results A 40–45% depletion in stercobilin in TS2-NEO fecal samples compared with controls was observed with p < 0.05; a less dramatic depletion was observed for stercobilinogen. Conclusions The results show that stercobilin depletion in feces is observed for an ASD mouse model vs. controls. This may help to explain recent observations of a less diverse microbiome in humans with ASD and may prove helpful in developing a clinical ASD biomarker. PMID:29147105

  12. Maintenance of basal levels of autophagy in Huntington's disease mouse models displaying metabolic dysfunction.

    Science.gov (United States)

    Baldo, Barbara; Soylu, Rana; Petersén, Asa

    2013-01-01

    Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein. Neuropathology in the basal ganglia and in the cerebral cortex has been linked to the motor and cognitive symptoms whereas recent work has suggested that the hypothalamus might be involved in the metabolic dysfunction. Several mouse models of HD that display metabolic dysfunction have hypothalamic pathology, and expression of mutant huntingtin in the hypothalamus has been causally linked to the development of metabolic dysfunction in mice. Although the pathogenic mechanisms by which mutant huntingtin exerts its toxic functions in the HD brain are not fully known, several studies have implicated a role for the lysososomal degradation pathway of autophagy. Interestingly, changes in autophagy in the hypothalamus have been associated with the development of metabolic dysfunction in wild-type mice. We hypothesized that expression of mutant huntingtin might lead to changes in the autophagy pathway in the hypothalamus in mice with metabolic dysfunction. We therefore investigated whether there were changes in basal levels of autophagy in a mouse model expressing a fragment of 853 amino acids of mutant huntingtin selectively in the hypothalamus using a recombinant adeno-associate viral vector approach as well as in the transgenic BACHD mice. We performed qRT-PCR and Western blot to investigate the mRNA and protein expression levels of selected autophagy markers. Our results show that basal levels of autophagy are maintained in the hypothalamus despite the presence of metabolic dysfunction in both mouse models. Furthermore, although there were no major changes in autophagy in the striatum and cortex of BACHD mice, we detected modest, but significant differences in levels of some markers in mice at 12 months of age. Taken together, our results indicate that overexpression of mutant huntingtin in mice do not significantly perturb basal levels of

  13. Gene therapy with IL-12 induced enhanced anti-tumor activity in fibrosarcoma mouse model.

    Science.gov (United States)

    Razi Soofiyani, Saiedeh; Kazemi, Tohid; Lotfipour, Farzaneh; Mohammad Hosseini, Akbar; Shanehbandi, Dariush; Hallaj-Nezhadi, Somayeh; Baradaran, Behzad

    2016-12-01

    Context Immunotherapy is among the most promising modalities for treatment of cancer. Recently, interleukin 12 (IL-12) has been used as an immunotherapeutic agent in cancer gene therapy. IL-12 can activate dendritic cells (DCs) and boost anti-tumor immune responses. Objective In the current study, we have investigated if IL-12 gene therapy can lead to the regression of tumor mass in a mouse model of fibrosarcoma. Material and methods To investigate the therapeutic efficacy of IL-12, WEHI-164 tumor cells were transfected with murine-IL12 plasmids using Lipofectamine. Enzyme linked immunosorbent assay (ELISA) was used to confirm IL-12 expression in transfected cells. The fibrosarcoma mouse model was established by subcutaneous injection of transfected cells to Balb/C mice. Mice were sacrificed and the tumors were extracted. Tumor sizes were measured by caliper. The expression of IL-12 and IFN-γ was studied with real-time PCR and western blotting. The expression of Ki-67(a tumor proliferation marker) in tumor mass was studied by immunohistochemistry staining. Results and discussion The group treated with IL-12 showed a significant decrease in tumor mass volume (P: 0.000). The results of real-time PCR and western blotting showed that IL-12 and IFN-γ expression increased in the group treated with IL-12 (relative expression of IL-12: 1.9 and relative expression of IFN-γ: 1.766). Immunohistochemistry staining showed that Ki-67 expression was reduced in the group treated with IL-12. Conclusion IL-12 gene therapy successfully led to regress of tumor mass in the fibrosarcoma mouse model. This may serve as a candidate therapeutic approach for treatment of cancer.

  14. PKC theta ablation improves healing in a mouse model of muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Luca Madaro

    Full Text Available Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C θ (PKCθ is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKCθ could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/θ(-/-, where PKCθ expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/θ(-/- mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKCθ expression in hematopoietic cells.These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKCθ activity in the development of DMD. Although the immune cell population(s involved remain unidentified, our findings reveal that PKCθ can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches.