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Sample records for a140v mouse model

  1. Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model [version 1; referees: 2 approved

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    Sampathkumar Rangasamy

    2016-09-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2 A140V “knock-in” mutant expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN cultures from mutant (Mecp2A140V/y and wild type (Mecp2+/y male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele. In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1 treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2  mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”.

  2. Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation

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    Blue Mary; Homanics Gregg E; Srivastava Nishit; Rice Stephen G; Olfers Shannon L; Jentarra Garilyn M; Naidu SakkuBai; Narayanan Vinodh

    2010-01-01

    Abstract Background Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurri...

  3. 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...

  4. Mouse models of medulloblastoma

    Institute of Scientific and Technical Information of China (English)

    Xiaochong Wu; Paul A. Northcott; Sidney Croul; Michael D. Taylor

    2011-01-01

    Medulloblastoma is the most common malignant pediatric brain tumor. Despite its prevalence and importance in pediatric neuro-oncology, the genes and pathways responsible for its initiation, maintenance,and progression remain poorly understood. Genetically engineered mouse models are an essential tool for uncovering the molecular and cellular basis of human diseases, including cancer, and serve a valuable role as preclinical models for testing targeted therapies. In this review, we summarize how such models have been successfully applied to the study of medulloblastoma over the past decade and what we might expect in the coming years.

  5. Mouse models of colorectal cancer

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    Yunguang Tong; Wancai Yang; H. Phillip Koeffler

    2011-01-01

    Colorectal cancer is one of the most common malignancies in the world. Many mouse models have been developed to evaluate features of colorectal cancer in humans. These can be grouped into genetically-engineered, chemically-induced, and inoculated models. However, none recapitulates all of the characteristics of human colorectal cancer. It is critical to use a specific mouse model to address a particular research question. Here, we review commonly used mouse models for human colorectal cancer.

  6. Mouse models for cancer research

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang; Lynette Moore; Ping Ji

    2011-01-01

    Mouse models of cancer enable researchers to leamn 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 Joumnal 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 overview of the development and applications of mouse models of cancer and directs the reader to upcoming papers describing the use of these models to be published in coming issues, beginning with three articles in the current issue.

  7. 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.

  8. 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. PMID:26063174

  9. 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.

  10. Mouse models of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States,and potent therapeutic options are lacking.Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer,currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed.In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes.In the last few years,several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed.These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer.Genetic alterations such as activating mutations in KRas,or TGFb and/or inactivation of tumoral suppressors such as p53,INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice.These mouse models have a spectrum of pathologic changes,from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system.These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches,chemopreventive and/or anticancer treatments.Here,we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

  11. 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.

  12. 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. PMID:26922998

  13. Mouse models of congenital cataract.

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    Graw, J

    1999-06-01

    Mouse mutants affecting lens development are excellent models for corresponding human disorders. The mutant aphakia has been characterised by bilaterally aphakic eyes (Varnum and Stevens, J Hered 1968;59:147-50); the corresponding gene was mapped to chromosome 19 (Varnum and Stevens, Mouse News Lett 1975;53:35). Recent investigations in our laboratory refined the linkage of 0.6 cM proximal to the marker D19Mit10. Several candidate genes have been excluded (Chuk1, Fgf8, Lbp1, Npm3, Pax2, Pitx3). The Cat3 mutations are characterised by vacuolated lenses caused by alterations in the initial secondary lens fibre cell differentiation. Secondary malformations develop at the cornea and iris, but the retina remains unaffected. The mutation has been mapped to chromosome 10 close to the markers D10Mit41 and D10Mit95. Several candidate genes have been excluded (Dcn, Elk3, Ldc, Mell8, Tr2-11). The series of Cat2 mutations have been mapped close to the gamma-crystallin genes (Cryg; Löster et al., Genomics 1994;23:240-2). The Cat2nop mutation is characterised by a mutation in the third exon of Crygb leading to a truncated gamma B-crystallin and the termination of lens fibre cell differentiation. The Cat2 mutants are interesting models for human cataracts caused by mutations in the human CRYG genes at chromosome 2q32-35. PMID:10627821

  14. Keratoacanthoma Pathobiology in Mouse Models

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    Katherine N. Gibson-Corley

    2014-05-01

    Full Text Available Recently we described skin tumors driven by skin-specific expression of Zmiz1 and here we define keratoacanthoma pathobiology in this mouse model. Similar to human keratoacanthoma development, we were able to segregate murine keratoacanthomas into three developmental phases: growth, maturation, and regression. These tumors had areas with cellular atypia, high mitotic rate, and minor local invasion in the growth phase, but with development they transitioned to maturation and regression phases with evidence of resolution. The early aggressive appearance could easily be misdiagnosed as a malignant change if the natural pathobiology was not well-defined in the model. To corroborate these findings in the Zmiz1 model, we examined squamous skin tumors from another tumor study in aging mice, and these tumors followed a similar biological progression. Lastly, we were able to evaluate the utility of the model to assess immune cell infiltration (F4/80, B220 Granzyme B, CD3 cells, arginase-1 in the regression phase; however, because inflammation was present at all phases of development, a more comprehensive approach will be needed in future investigations. Our study of keratoacanthomas in selected murine models suggests that these squamous tumors can appear histologically aggressive during early development, but with time will enter a regression phase indicating a benign biology. Importantly, studies of squamous skin tumor models should be cautious in tumor diagnosis as the early growth distinction between malignant versus benign based solely on histopathology may not be easily discerned without longitudinal studies to confirm the tumor pathobiology.

  15. Mouse model of intracerebellar haemorrhage.

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    Tijjani Salihu, Abubakar; Muthuraju, Sangu; Aziz Mohamed Yusoff, Abdul; Ahmad, Farizan; Zulkifli Mustafa, Mohd; Jaafar, Hasnan; Idris, Zamzuri; Rahman Izaini Ghani, Abdul; Malin Abdullah, Jafri

    2016-10-01

    The present study aimed to investigate the behavior and neuronal morphological changes in the perihaemorrhagic tissue of the mouse intracerebellar haemorrhage experimental model. Adult male Swiss albino mice were stereotactically infused with collagenase type VII (0.4U/μl of saline) unilaterally in to the cerebellum, following anaesthesia. Motor deficits were assessed using open field and composite score for evaluating the mouse model of cerebellar ataxia at 1, 3, 7, 14 and 21 days after collagenase infusion. The animals were sacrificed at the same time interval for evaluation of perihaematomal neuronal degeneration using haematoxylin and eosin staining and Annexin V-FITC/Propidium iodide assay. At the end of the study, it was found that infusion of 0.4U collagenase produces significant locomotor and ataxic deficit in the mice especially within the first week post surgery, and that this gradually improved within three weeks. Neuronal degeneration evident by cytoplasmic shrinkage and nuclear pyknosis was observed at the perihaematomal area after one day; especially at 3 and 7 days post haemorrhage. By 21 days, both the haematoma and degenerating neurons in the perihaematomal area were phagocytosed and the remaining neuronal cells around the scar tissue appeared normal. Moreover, Annexin-V/propidium iodide-positive cells were observed at the perihaematomal area at 3 and 7 days implying that the neurons likely die via apoptosis. It was concluded that a population of potentially salvageable neurons exist in the perihaematomal area after cerebellar haemorrhage throughout a wide time window that could be amenable to treatment. PMID:27327104

  16. Mouse Models for Filovirus Infections

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    Kelly L. Warfield

    2012-09-01

    Full Text Available 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.

  17. Development of Orthotopic Pancreatic Tumor Mouse Models

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    Qiu, Wanglong; Gloria H. Su

    2013-01-01

    Genetically engineered mouse models of pancreatic cancer that recapitulate human pancreatic tumorigenesis have been established. However, the cost associated with generating and housing these mice can be prohibitive. Tumor latency and progression to invasive diseases in these models are also highly variable. Xenograft mouse models of human pancreatic cancer including heterotopic and orthotopic have been widely used in preclinical studies for their comparatively low cost and rapid, predictable...

  18. 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...... similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now, 57 years after the first report on the wobbler mouse we summarize the progress made in understanding...

  19. Mouse models in male fertility research

    Institute of Scientific and Technical Information of China (English)

    Duangporn Jamsai; Moira K O'Bryan

    2011-01-01

    Limited knowledge of the genetic causes of male infertility has resulted in few treatment and targeted therapeutic options.Although the ideal approach to identify infertility causing mutations is to conduct studies in the human population,this approach has progressed slowly due to the limitations described herein.Given the complexity of male fertility,the entire process cannot be modeled in vitro.As such,animal models,in particular mouse models,provide a valuable alternative for gene identification and experimentation.Since the introduction of molecular biology and recent advances in animal model production,there has been a substantial acceleration in the identification and characterization of genes associated with many diseases,including infertility.Three major types of mouse models are commonly used in biomedical research,including knockout/knockin/gene-trapped,transgenic and chemical-induced point mutant mice.Using these mouse models,over 400 genes essential for male fertility have been revealed.It has,however,been estimated that thousands of genes are involved in the regulation of the complex process of male fertility,as many such genes remain to be characterized.The current review is by no means a comprehensive list of these mouse models,rather it contains examples of how mouse models have advanced our knowledge of post-natal germ cell development and male fertility regulation.

  20. The wobbler mouse, an ALS animal model

    OpenAIRE

    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 similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now,...

  1. Citrobacter rodentium mouse model of bacterial infection.

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    Crepin, Valerie F; Collins, James W; Habibzay, Maryam; Frankel, Gad

    2016-10-01

    Infection of mice with Citrobacter rodentium is a robust model to study bacterial pathogenesis, mucosal immunology, the health benefits of probiotics and the role of the microbiota during infection. C. rodentium was first isolated by Barthold from an outbreak of mouse diarrhea in Yale University in 1972 and was 'rediscovered' by Falkow and Schauer in 1993. Since then the use of the model has proliferated, and it is now the gold standard for studying virulence of the closely related human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively). Here we provide a detailed protocol for various applications of the model, including bacterial growth, site-directed mutagenesis, mouse inoculation (from cultured cells and after cohabitation), monitoring of bacterial colonization, tissue extraction and analysis, immune responses, probiotic treatment and microbiota analysis. The main protocol, from mouse infection to clearance and analysis of tissues and host responses, takes ∼5 weeks to complete. PMID:27606775

  2. Genetically engineered mouse models of pituitary tumors

    OpenAIRE

    DavidACano; AlfonsoSoto-Moreno

    2014-01-01

    Animal models constitute valuable tools for investigating the pathogenesis of cancer as well as for preclinical testing of novel therapeutics approaches. However, the pathogenic mechanisms of pituitary tumor formation remain poorly understood, particularly in sporadic adenomas, thus making it a challenge to model pituitary tumors in mice. Nevertheless, genetically engineered mouse models (GEMMs) of pituitary tumors have provided important insight into pituitary tumor biology. In this paper, w...

  3. Genetically engineered mouse models of prostate cancer

    NARCIS (Netherlands)

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

    2008-01-01

    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:

  4. Mouse Models of Diabetic Nephropathy

    OpenAIRE

    Brosius, Frank C.; Alpers, Charles E.; Bottinger, Erwin P.; Breyer, Matthew D.; Coffman, Thomas M.; Gurley, Susan B.; Harris, Raymond C.; Kakoki, Masao; Kretzler, Matthias; Leiter, Edward H.; Levi, Moshe; McIndoe, Richard A.; Sharma, Kumar; Smithies, Oliver; Susztak, Katalin

    2009-01-01

    Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Despite its prevalence, identification of specific factors that cause or predict diabetic nephropathy has been delayed in part by lack of reliable animal models that mimic the disease in humans. The Animal Models of Diabetic Complications Consortium (AMDCC) was created 8 years ago by the National Institutes of Health to develop and characterize models of diabetic nephropathy and other complications. This interim rep...

  5. Engineering a new mouse model for vitiligo.

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    Manga, Prashiela; Orlow, Seth J

    2012-07-01

    Although the precise mechanisms that trigger vitiligo remain elusive, autoimmune responses mediate its progression. The development of therapies has been impeded by a paucity of animal models, since mice lack interfollicular melanocytes, the primary targets in vitiligo. In this issue, Harris et al. describe a mouse model in which interfollicular melanocytes are retained by Kit ligand overexpression and an immune response is initiated by transplanting melanocyte-targeting CD8+ T cells.

  6. Mouse kidney transplantation: models of allograft rejection.

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    Tse, George H; Hesketh, Emily E; Clay, Michael; Borthwick, Gary; Hughes, Jeremy; Marson, Lorna P

    2014-01-01

    Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

  7. Mouse Models for Filovirus Infections

    OpenAIRE

    Kelly L Warfield; Bradfute, Steven B; Mike Bray

    2012-01-01

    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 filovir...

  8. Mouse Genetic Models of Human Brain Disorders

    OpenAIRE

    Celeste eLeung; Zhengping eJia

    2016-01-01

    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, intellectua...

  9. Digenic Inheritance in Cystinuria Mouse Model.

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    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.

  10. Mouse models of anemia of cancer.

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    Airie Kim

    Full Text Available Anemia of cancer (AC may contribute to cancer-related fatigue and impair quality of life. Improved understanding of the pathogenesis of AC could facilitate better treatment, but animal models to study AC are lacking. We characterized four syngeneic C57BL/6 mouse cancers that cause AC. Mice with two different rapidly-growing metastatic lung cancers developed the characteristic findings of anemia of inflammation (AI, with dramatically different degrees of anemia. Mice with rapidly-growing metastatic melanoma also developed a severe anemia by 14 days, with hematologic and inflammatory parameters similar to AI. Mice with a slow-growing peritoneal ovarian cancer developed an iron-deficiency anemia, likely secondary to chronically impaired nutrition and bleeding into the peritoneal cavity. Of the four models, hepcidin mRNA levels were increased only in the milder lung cancer model. Unlike in our model of systemic inflammation induced by heat-killed Brucella abortus, ablation of hepcidin in the ovarian cancer and the milder lung cancer mouse models did not affect the severity of anemia. Hepcidin-independent mechanisms play an important role in these murine models of AC.

  11. Mouse models of intestinal inflammation and cancer.

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    Westbrook, Aya M; Szakmary, Akos; Schiestl, Robert H

    2016-09-01

    Chronic inflammation is strongly associated with approximately one-fifth 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

  12. A mouse model of in utero transplantation.

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    Nijagal, Amar; Le, Tom; Wegorzewska, Marta; Mackenzie, Tippi C

    2011-01-01

    The transplantation of stem cells and viruses in utero has tremendous potential for treating congenital disorders in the human fetus. For example, in utero transplantation (IUT) of hematopoietic stem cells has been used to successfully treat patients with severe combined immunodeficiency. In several other conditions, however, IUT has been attempted without success. Given these mixed results, the availability of an efficient non-human model to study the biological sequelae of stem cell transplantation and gene therapy is critical to advance this field. We and others have used the mouse model of IUT to study factors affecting successful engraftment of in utero transplanted hematopoietic stem cells in both wild-type mice and those with genetic diseases. The fetal environment also offers considerable advantages for the success of in utero gene therapy. For example, the delivery of adenoviral, adeno-associated viral, retroviral, and lentiviral vectors into the fetus has resulted in the transduction of multiple organs distant from the site of injection with long-term gene expression. in utero gene therapy may therefore be considered as a possible treatment strategy for single gene disorders such as muscular dystrophy or cystic fibrosis. Another potential advantage of IUT is the ability to induce immune tolerance to a specific antigen. As seen in mice with hemophilia, the introduction of Factor IX early in development results in tolerance to this protein. In addition to its use in investigating potential human therapies, the mouse model of IUT can be a powerful tool to study basic questions in developmental and stem cell biology. For example, one can deliver various small molecules to induce or inhibit specific gene expression at defined gestational stages and manipulate developmental pathways. The impact of these alterations can be assessed at various timepoints after the initial transplantation. Furthermore, one can transplant pluripotent or lineage specific progenitor

  13. Criteria for Validating Mouse Models of Psychiatric Diseases

    OpenAIRE

    Chadman, Kathryn K.; Yang, Mu; Crawley, Jacqueline N.

    2009-01-01

    Animal models of human diseases are in widespread use for biomedical research. Mouse models with a mutation in a single gene or multiple genes are excellent research tools for understanding the role of a specific gene in the etiology of a human genetic disease. Ideally, the mouse phenotypes will recapitulate the human phenotypes exactly. However, exact matches are rare, particularly in mouse models of neuropsychiatric disorders. This article summarizes the current strategies for optimizing th...

  14. Quantitative bioluminescence imaging of mouse tumor models.

    Science.gov (United States)

    Tseng, Jen-Chieh; Kung, Andrew L

    2015-01-05

    Bioluminescence imaging (BLI) has become an essential technique for preclinical evaluation of anticancer therapeutics and provides sensitive and quantitative measurements of tumor burden in experimental cancer models. For light generation, a vector encoding firefly luciferase is introduced into human cancer cells that are grown as tumor xenografts in immunocompromised hosts, and the enzyme substrate luciferin is injected into the host. Alternatively, the reporter gene can be expressed in genetically engineered mouse models to determine the onset and progression of disease. In addition to expression of an ectopic luciferase enzyme, bioluminescence requires oxygen and ATP, thus only viable luciferase-expressing cells or tissues are capable of producing bioluminescence signals. Here, we summarize a BLI protocol that takes advantage of advances in hardware, especially the cooled charge-coupled device camera, to enable detection of bioluminescence in living animals with high sensitivity and a large dynamic range.

  15. A Transgenic Mouse Model of Poliomyelitis.

    Science.gov (United States)

    Koike, Satoshi; Nagata, Noriyo

    2016-01-01

    Transgenic mice (tg mice) that express the human poliovirus receptor (PVR), CD155, are susceptible to poliovirus and develop a neurological disease that resembles human poliomyelitis. Assessment of the neurovirulence levels of poliovirus strains, including mutant viruses produced by reverse genetics, circulating vaccine-derived poliovirus, and vaccine candidates, is useful for basic research of poliovirus pathogenicity, the surveillance of circulating polioviruses, and the quality control of oral live poliovirus vaccines, and does not require the use of monkeys. Furthermore, PVR-tg mice are useful for studying poliovirus tissue tropism and host immune responses. PVR-tg mice can be bred with mice deficient in the genes involved in viral pathogenicity. This report describes the methods used to analyze the pathogenicity and immune responses of poliovirus using the PVR-tg mouse model. PMID:26983733

  16. A mouse model for testing remyelinating therapies.

    Science.gov (United States)

    Bai, C Brian; Sun, Sunny; Roholt, Andrew; Benson, Emily; Edberg, Dale; Medicetty, Satish; Dutta, Ranjan; Kidd, Grahame; Macklin, Wendy B; Trapp, Bruce

    2016-09-01

    Used in combination with immunomodulatory therapies, remyelinating therapies are a viable therapeutic approach for treating individuals with multiple sclerosis. Studies of postmortem MS brains identified greater remyelination in demyelinated cerebral cortex than in demyelinated brain white matter and implicated reactive astrocytes as an inhibitor of white matter remyelination. An animal model that recapitulates these phenotypes would benefit the development of remyelination therapeutics. We have used a modified cuprizone protocol that causes a consistent and robust demyelination of mouse white matter and cerebral cortex. Spontaneous remyelination occurred significantly faster in the cerebral cortex than in white matter and reactive astrocytes were more abundant in white matter lesions. Remyelination of white matter and cerebral cortex was therapeutically enhanced by daily injections of thyroid hormone triiodothyronine (T3). In summary, we describe an in vivo demyelination/remyelination paradigm that can be powered to determine efficacy of therapies that enhance white matter and cortical remyelination. PMID:27384502

  17. Preclinical fluorescent mouse models of pancreatic cancer

    Science.gov (United States)

    Bouvet, Michael; Hoffman, Robert M.

    2007-02-01

    Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

  18. Mouse models for BRAF-induced cancers.

    Science.gov (United States)

    Pritchard, C; Carragher, L; Aldridge, V; Giblett, S; Jin, H; Foster, C; Andreadi, C; Kamata, T

    2007-11-01

    Oncogenic mutations in the BRAF gene are detected in approximately 7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine-->glutamate mutation at residue 600 ((V600E)BRAF). In cells cultured in vitro, (V600E)BRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that (V600E)BRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.

  19. Characterization of a mouse model of headache.

    Science.gov (United States)

    Huang, Dongyue; Ren, Lynn; Qiu, Chang-Shen; Liu, Ping; Peterson, Jonathan; Yanagawa, Yuchio; Cao, Yu-Qing

    2016-08-01

    Migraine and other primary headache disorders affect a large population and cause debilitating pain. Establishing animal models that display behavioral correlates of long-lasting and ongoing headache, the most common and disabling symptom of migraine, is vital for the elucidation of disease mechanisms and identification of drug targets. We have developed a mouse model of headache, using dural application of capsaicin along with a mixture of inflammatory mediators (IScap) to simulate the induction of a headache episode. This elicited intermittent head-directed wiping and scratching as well as the phosphorylation of c-Jun N-terminal kinase in trigeminal ganglion neurons. Interestingly, dural application of IScap preferentially induced FOS protein expression in the excitatory but not inhibitory cervical/medullary dorsal horn neurons. The duration of IScap-induced behavior and the number of FOS-positive neurons correlated positively in individual mice; both were reduced to the control level by the pretreatment of antimigraine drug sumatriptan. Dural application of CGRP(8-37), the calcitonin gene-related peptide (CGRP) receptor antagonist, also effectively blocked IScap-induced behavior, which suggests that the release of endogenous CGRP in the dura is necessary for IScap-induced nociception. These data suggest that dural IScap-induced nocifensive behavior in mice may be mechanistically related to the ongoing headache in humans. In addition, dural application of IScap increased resting time in female mice. Taken together, we present the first detailed study using dural application of IScap in mice. This headache model can be applied to genetically modified mice to facilitate research on the mechanisms and therapeutic targets for migraine headache. PMID:27058678

  20. Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

    OpenAIRE

    Fujii, Ken; Nagata, Noriyo; Sato, Yuko; Ong, Kien Chai; Wong, Kum Thong; Yamayoshi, Seiya; Shimanuki, Midori; Shitara, Hiroshi; Taya, Choji; KOIKE, Satoshi

    2013-01-01

    EV71 infection with severe neurological complications has become a serious public health concern. However, suitable small animal models to study human EV71 pathogenesis are not available. We have generated a Tg mouse model by expressing the human EV71 receptor, Scavenger receptor B2, and found it to be susceptible to EV71 infection. This Tg mouse model exhibits neurological disease and pathology very similar to that observed in humans. The results confirm that the Scavenger receptor B2 recept...

  1. 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.

  2. 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.

  3. Behavioral phenotypes of genetic mouse models of autism.

    Science.gov (United States)

    Kazdoba, T M; Leach, P T; Crawley, J N

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism.

  4. Mouse Models for Studying the Formation and Propagation of Prions*

    OpenAIRE

    Watts, JC; Prusiner, SB

    2014-01-01

    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 mode...

  5. Development and testing of a mouse simulated space flight model

    Science.gov (United States)

    Sonnenfeld, Gerald

    1987-01-01

    The development and testing of a mouse model for simulating some aspects of weightlessness that occurs during space flight, and the carrying out of immunological experiments on animals undergoing space flight is examined. The mouse model developed was an antiorthostatic, hypokinetic, hypodynamic suspension model similar to one used with rats. The study was divided into two parts. The first involved determination of which immunological parameters should be observed on animals flown during space flight or studied in the suspension model. The second involved suspending mice and determining which of those immunological parameters were altered by the suspension. Rats that were actually flown in Space Shuttle SL-3 were used to test the hypotheses.

  6. 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

  7. CML Mouse Model Generated from Leukemia Stem Cells.

    Science.gov (United States)

    Hu, Yiguo

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a high number of well-differentiated neutrophils in peripheral blood and myeloid cells in bone marrow (BM). CML is derived from the hematopoietic stem cells (HSCs) with the Philadelphia chromosome (Ph(+), t(9;22)-(q34;q11)), resulting in generating a fusion oncogene, BCR/ABL1. HSCs with Ph(+) are defined as leukemia stem cells (LSCs), a subpopulation cell at the apex of hierarchies in leukemia cells and responsible for the disease continuous propagation. Several kinds of CML models have been developed to reveal the mechanism of CML pathogenesis and evaluate therapeutic drugs in the past three decades. Here, we describe the procedures to generate a CML mouse model by introducing BCR/ABL1 into Lin(-)Sca1(+) cKit(+) population cells purified from mouse bone marrow. In CML retroviral transduction/transplantation mouse models, this modified model can mimic CML pathogenesis on high fidelity. PMID:27581136

  8. Application of hepatitis B virus replication mouse model

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To evaluate the value of the hepatitis B virus(HBV) replication mouse model with regard to several aspects of the study of HBV biology.METHODS:To evaluate the HBV replication mouse model in detecting the efficacy of anti-HBV agents,the interferon inducer polyinosinic-polytidylin acid(polyIC) and nucleotide analogues adefovir and entecavir were administered to mice injected with wild type pHBV4.1,and the inhibiting effect of these agents on HBV DNA replication was evaluated.To identify the model's value ...

  9. Parkinson’s disease mouse models in translational research

    OpenAIRE

    Antony, Paul; Diederich, Nico; Balling, Rudi

    2011-01-01

    Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to addres...

  10. Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

  11. 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.

  12. Virtues and limitations of the preimplantation mouse embryo as a model system

    OpenAIRE

    Robert A Taft

    2007-01-01

    The mouse is the most widely used model of preimplantation embryo development, but is it a good model? Its small size, prolificacy and ease of handling make the mouse a relatively low cost, readily available and attractive alternative when embryos from other species are difficult or expensive to obtain. However, the real power of the mouse as a model lies in mouse genetics. The development of inbred mouse strains facilitated gene discovery as well as our understanding of gene function and reg...

  13. Mouse Models of Neurofibromatosis 1 and 2

    Directory of Open Access Journals (Sweden)

    David H. Gutmann

    2002-01-01

    Full Text Available The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1 are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2 develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors.

  14. A Neural Model of Demyelination of the Mouse Spinal Cord

    OpenAIRE

    Petreska, Biljana; Yovel, Yossi

    2008-01-01

    This paper presents a neural network model of demyelination of the mouse motor pathways, coupled to a central pattern generation (CPG) model for quadruped walking. Demyelination is the degradation of the myelin layer covering the axons which can be caused by several neurodegenerative autoimmune diseases such as multiple sclerosis. We use this model - to our knowledge first of its kind - to investigate the locomotion deficits that appear following demyelination of axons in the spinal cord. Our...

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

    NARCIS (Netherlands)

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

    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 Sjogren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno-associated vi

  17. CHARACTERIZATION OF AEROMONAS VIRULENCE USING AN IMMUNOCOMPROMISED MOUSE MODEL

    Science.gov (United States)

    An immunocompromised mouse model was used to characterize Aeromonas strains for their ability to cause opportunistic, extraintestinal infections. A total of 34 isolates of Aeromonas (A. hydrophila [n = 12]), A. veronii biotype sobria [n = 7], A. caviae [n = 4], A. enchelia [n = 4...

  18. Rapid genetic algorithm optimization of a mouse computational model: Benefits for anthropomorphization of neonatal mouse cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Corina Teodora Bot

    2012-11-01

    Full Text Available 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.

  19. Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects

    NARCIS (Netherlands)

    Korstanje, Ron; Desai, Jigar; Lazar, Gloria; King, Benjamin; Rollins, Jarod; Spurr, Melissa; Joseph, Jamie; Kadambi, Sindhuja; Li, Yang; Cherry, Allison; Matteson, Paul G.; Paigen, Beverly; Millonig, James H.

    2008-01-01

    Korstanje R, Desai J, Lazar G, King B, Rollins J, Spurr M, Joseph J, Kadambi S, Li Y, Cherry A, Matteson PG, Paigen B, Millonig JH. Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects. Physiol Genomics 35: 296-30

  20. Current Concepts: Mouse Models of Sjögren's Syndrome

    Directory of Open Access Journals (Sweden)

    Tegan N. Lavoie

    2011-01-01

    Full Text Available Sjögren's syndrome (SjS is a complex chronic autoimmune disease of unknown etiology which primarily targets the exocrine glands, resulting in eventual loss of secretory function. The disease can present as either primary SjS or secondary SjS, the latter of which occurs concomitantly with another autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or primary biliary cirrhosis. Current advancements in therapeutic prevention and treatment for SjS are impeded by lack of understanding in the pathophysiological and clinical progression of the disease. Development of appropriate mouse models for both primary and secondary SjS is needed in order to advance knowledge of this disease. This paper details important features, advantages, and pitfalls of current animal models of SjS, including spontaneous, transgenic, knockout, immunization, and transplantation chimera mouse models, and emphasizes the need for a better model in representing the human SjS phenotype.

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

    OpenAIRE

    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.

    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 respon...

  2. A mouse model for HBV immunotolerance and immunotherapy

    OpenAIRE

    Yang, Dan; Liu, Longchao; Zhu, Danming; Peng, Hua; Su, Lishan; Fu, Yang-Xin; Zhang, Liguo

    2013-01-01

    Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization wit...

  3. Retinoic acid fails to reverse emphysema in adult mouse models

    OpenAIRE

    Fujita, M; Ye, Q.; Ouchi, H.; Nakashima, N; Hamada, N; Hagimoto, N; Kuwano, K.; Mason, R.; Nakanishi, Y

    2004-01-01

    Methods: The models used were an elastase induced emphysema model for acute alveolar destruction and a tumour necrosis factor (TNF)-α transgenic mouse which exhibits chronic air space enlargement, loss of elastic recoil, increased lung volume, and pulmonary hypertension comparable to human pulmonary emphysema. All-trans-retinoic acid (2 mg/kg) was injected for 12 successive days after the establishment of emphysema. The effects of treatment were evaluated using physiological and morphometric ...

  4. Quantification of mouse pulmonary cancer models by microcomputed tomography imaging

    International Nuclear Information System (INIS)

    The advances in preclinical cancer models, including orthotopic implantation models or genetically engineered mouse models of cancer, enable pursuing the molecular mechanism of cancer disease that might mimic genetic and biological processes in humans. Lung cancer is the major cause of cancer deaths; therefore, the treatment and prevention of lung cancer are expected to be improved by a better understanding of the complex mechanism of disease. In this study, we have examined the quantification of two distinct mouse lung cancer models by utilizing imaging modalities for monitoring tumor progression and drug efficacy evaluation. The utility of microcomputed tomography (micro-CT) for real-time/non-invasive monitoring of lung cancer progression has been confirmed by combining bioluminescent imaging and histopathological analyses. Further, we have developed a more clinically relevant lung cancer model by utilizing K-rasLSL-G12D/p53LSL-R270H mutant mice. Using micro-CT imaging, we monitored the development and progression of solitary lung tumor in K-rasLSL-G12D/p53LSL-R270H mutant mouse, and further demonstrated tumor growth inhibition by anticancer drug treatment. These results clearly indicate that imaging-guided evaluation of more clinically relevant tumor models would improve the process of new drug discovery and increase the probability of success in subsequent clinical studies. (author)

  5. Mouse models for atherosclerosis and pharmaceutical modifiers

    NARCIS (Netherlands)

    Zadelaar, A.S.M.; Kleemann, R.; Verschuren, L.; Vries-van der Weij, J. de; Hoorn, J. van der; Princen, H.M.; Kooistra, T.

    2007-01-01

    Atherosclerosis is a multifactorial highly-complex disease with numerous etiologies that work synergistically to promote lesion development. The ability to develop preventive and ameliorative treatments will depend on animal models that mimic the human subject metabolically and pathophysiologically

  6. Osthole suppresses seizures in the mouse maximal electroshock seizure model.

    Science.gov (United States)

    Luszczki, Jarogniew J; Andres-Mach, Marta; Cisowski, Wojciech; Mazol, Irena; Glowniak, Kazimierz; Czuczwar, Stanislaw J

    2009-04-01

    The aim of this study was to determine the anticonvulsant effects of osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one]--a natural coumarin derivative} in the mouse maximal electroshock-induced seizure model. The antiseizure effects of osthole were determined at 15, 30, 60, and 120 min after its systemic (i.p.) administration. Time course of anticonvulsant action of osthole revealed that the natural coumarin derivative produced a clear-cut antielectroshock activity in mice and the experimentally-derived ED(50) values for osthole ranged from 259 to 631 mg/kg. In conclusion, osthole suppresses seizure activity in the mouse maximal electroshock-induced seizure model. It may become a novel treatment option following further investigation in other animal models of epilepsy and preclinical studies. PMID:19236860

  7. Molecular imaging of vessels in mouse models of disease

    International Nuclear Information System (INIS)

    Vascular imaging of angiogenesis in mouse models of disease requires multi modal imaging hardware capable of targeting both structure and function at different physical scales. The three dimensional (3D) structure and function vascular information allows for accurate differentiation between biological processes. For example, image analysis of vessel development in angiogenesis vs. arteriogenesis enables more accurate detection of biological variation between subjects and more robust and reliable diagnosis of disease. In the recent years a number of micro imaging modalities have emerged in the field as preferred means for this purpose. They provide 3D volumetric data suitable for analysis, quantification, validation, and visualization of results in animal models. This review highlights the capabilities of microCT, ultrasound and microPET for multimodal imaging of angiogenesis and molecular vascular targets in a mouse model of tumor angiogenesis. The basic principles of the imaging modalities are described and experimental results are presented.

  8. 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 expres

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

    DEFF Research Database (Denmark)

    Jepsen, Jesper; Kindler, Ekkart

    2015-01-01

    The Event Coordination Notation (ECNO) allows modelling the desired behaviour of a software system on top of any object-oriented software. Together with existing technologies from Model-based Software Engineering (MBSE) for automatically generating the software for the structural parts, ECNO allows...... management system. This way, we demonstrate that ECNO can be used for modelling software beyond the typical Mickey Mouse examples. This example demonstrates that the essence of workflow management – including its behaviour – can be captured in ECNO: in a sense, it is a domain model of workflow management...

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

    Science.gov (United States)

    Paschall, Amy V; Liu, Kebin

    2016-01-01

    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. PMID:27584043

  11. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    Science.gov (United States)

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely “functional,” i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  12. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    Science.gov (United States)

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely "functional," i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  13. 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.

  14. 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.

  15. Genetically modified mouse models for premature ovarian failure (POF).

    Science.gov (United States)

    Jagarlamudi, Krishna; Reddy, Pradeep; Adhikari, Deepak; Liu, Kui

    2010-02-01

    Premature ovarian failure (POF) is a complex disorder that affects approximately 1% of women. POF is characterized by the depletion of functional ovarian follicles before the age of 40 years, and clinically, patients may present with primary amenorrhea or secondary amenorrhea. Although some genes have been hypothesized to be candidates responsible for POF, the etiology of most of the cases is idiopathic, with the underlying causes still unidentified because of the heterogeneity of the disease. In this review, we consider some mutant mouse models that exhibit phenotypes which are comparable to human POF, and we suggest that the use of these mouse models may help us to gain a better understanding of the molecular mechanisms underlying POF in humans.

  16. Sleep Phenotyping in a Mouse Model of Extreme Trait Anxiety

    OpenAIRE

    Jakubcakova, Vladimira; Flachskamm, Cornelia; Landgraf, Rainer; Kimura, Mayumi

    2012-01-01

    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 (NA...

  17. Cardiac Dysfunction in the BACHD Mouse Model of Huntington's Disease

    OpenAIRE

    Schroeder, Analyne M.; Huei Bin Wang; Saemi Park; Jordan, Maria C.; Fuying Gao; Giovanni Coppola; Fishbein, Michael C; Kenneth P Roos; Ghiani, Cristina A.; Colwell, Christopher S.

    2016-01-01

    While Huntington’s disease (HD) is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD ...

  18. A mouse model of intestinal stem cell function and regeneration

    OpenAIRE

    Slorach, E M; Campbell, F. C.; Dorin, J. R.

    1999-01-01

    We present here an in vivo mouse model for intestinal stem cell function and differentiation that uses postnatal intestinal epithelial cell aggregates to generate a differentiated murine small intestinal mucosa with full crypt-villus architecture. The process of neomucosal formation is highly similar to that of intestinal regeneration. Both in vivo grafting and primary culture of these cells reveal two different epithelial cell populations, which display properties consistent with intestinal ...

  19. Predictably irrational: assaying cognitive inflexibility in mouse models of schizophrenia

    OpenAIRE

    Brigman, Jonathan L.

    2010-01-01

    The development of sophisticated, translatable mouse-based assays modeling the behavioral manifestations of neuropsychiatric diseases such as schizophrenia has lagged the advances in molecular and genomic techniques. Our laboratory has made efforts to fill this gap by investing in the development of novel assays, including adapting a touchscreen-based method for measuring cognitive and executive functions for use in mice. As part of these efforts, a recent study by Brigman et al. (2009) inv...

  20. Substrate reduction therapy in mouse models of the glycosphingolipidoses.

    OpenAIRE

    Platt, Frances M.; Jeyakumar, Mylvaganam; Andersson, Ulrika; Heare, Tanya; Dwek, Raymond A.; Butters, Terry D.

    2003-01-01

    Substrate reduction therapy uses small molecules to slow the rate of glycolipid biosynthesis. One of these drugs, N-butyldeoxynojirimycin (NB-DNJ), shows efficacy in mouse models of Tay-Sachs, Sandhoff and Fabry diseases. This offers the prospect that NB-DNJ may be of therapeutic benefit, at least in the juvenile and adult onset variants of these disorders. The infantile onset variants will require an additional enzyme-augmenting modality if the pathology is to be significantly improved. A se...

  1. Extracting Extra-Telomeric Phenotypes from Telomerase Mouse Models

    OpenAIRE

    Sung, Young Hoon; Ali, Muhammad; Lee, Han-Woong

    2013-01-01

    Telomerase reverse transcriptase (TERT) is the protein component of telomerase and combined with an RNA molecule, telomerase RNA component, forms the telomerase enzyme responsible for telomere elongation. Telomerase is essential for maintaining telomere length from replicative attrition and thus contributes to the preservation of genome integrity. Although diverse mouse models have been developed and studied to prove the physiological roles of telomerase as a telomere-elongating enzyme, recen...

  2. Chondroprotective effects of Salubrinal in a mouse model of osteoarthritis

    OpenAIRE

    K. HAMAMURA; Nishimura, A; Iino, T; Takigawa, S.; SUDO, A.; Yokota, H

    2015-01-01

    Objectives Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthri...

  3. Real-Time Bioluminescence Imaging of Nitroreductase in Mouse Model.

    Science.gov (United States)

    Feng, Ping; Zhang, Huateng; Deng, Quankun; Liu, Wei; Yang, Linghui; Li, Guobo; Chen, Guo; Du, Lupei; Ke, Bowen; Li, Minyong

    2016-06-01

    Nitroreductase (NTR) is an endogenous reductase overexpressed in hypoxic tumors; however, its precise detection in living cells and animals remains a considerable challenge. Herein, we developed three reaction-based probes and a related bioluminescence assay for the real-time NTR detection. The high sensitivity and selectivity of probe 3, combined with its remarkable potential of bioluminescence imaging, affords a valuable approach for in vivo imaging of NTR in a tumor model mouse. PMID:27197544

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

    OpenAIRE

    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 would express anhedonia, induced by chronic stress. Mice were repeatedly exposed to the non-physical presence of a rat. Alterations in stress system activity were measured. Anhedonia was assessed ...

  5. Real-Time Bioluminescence Imaging of Nitroreductase in Mouse Model.

    Science.gov (United States)

    Feng, Ping; Zhang, Huateng; Deng, Quankun; Liu, Wei; Yang, Linghui; Li, Guobo; Chen, Guo; Du, Lupei; Ke, Bowen; Li, Minyong

    2016-06-01

    Nitroreductase (NTR) is an endogenous reductase overexpressed in hypoxic tumors; however, its precise detection in living cells and animals remains a considerable challenge. Herein, we developed three reaction-based probes and a related bioluminescence assay for the real-time NTR detection. The high sensitivity and selectivity of probe 3, combined with its remarkable potential of bioluminescence imaging, affords a valuable approach for in vivo imaging of NTR in a tumor model mouse.

  6. A Mouse Model of Zika Virus Pathogenesis.

    Science.gov (United States)

    Lazear, Helen M; Govero, Jennifer; Smith, Amber M; Platt, Derek J; Fernandez, Estefania; Miner, Jonathan J; Diamond, Michael S

    2016-05-11

    The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3(-/-)Irf5(-/-)Irf7(-/-) triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1(-/-)) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3(-/-), Irf5(-/-), and Mavs(-/-) knockout mice exhibited no overt illness. Ifnar1(-/-) mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1(-/-) mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis. PMID:27066744

  7. Behavioral characterization of mouse models of neuroferritinopathy.

    Directory of Open Access Journals (Sweden)

    Sara Capoccia

    Full Text Available Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK promoter. Transgenic (Tg mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests. The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help

  8. Behavioral characterization of mouse models of neuroferritinopathy.

    Science.gov (United States)

    Capoccia, Sara; Maccarinelli, Federica; Buffoli, Barbara; Rodella, Luigi F; Cremona, Ottavio; Arosio, Paolo; Cirulli, Francesca

    2015-01-01

    Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing

  9. 77 FR 24499 - Government-Owned Inventions; Availability for Licensing: Mouse Models

    Science.gov (United States)

    2012-04-24

    ....gov . Sirt3 Knockout (Sirt3\\tm1.1Cxd\\) Mouse Model for Cardiology and Metabolism Studies Description... Applications: Cardiology, Metabolism. Developer of Mouse: Chuxia Deng, Ph.D. (NIDDK). Relevant Publication:...

  10. Mouse models of dengue virus infection for vaccine testing.

    Science.gov (United States)

    Sarathy, Vanessa V; Milligan, Gregg N; Bourne, Nigel; Barrett, Alan D T

    2015-12-10

    Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the interferon-α/β receptor (IFN-α/β R) and the interferon-γ receptor (IFN-γR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-α/βR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple

  11. Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

    International Nuclear Information System (INIS)

    Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.

  12. New Mouse Model for Dengue Virus Vaccine Testing

    OpenAIRE

    Johnson, Alison J.; Roehrig, John T.

    1999-01-01

    Several dengue (DEN) virus vaccines are in development; however, the lack of a reliable small animal model in which to test them is a major obstacle. Because evidence suggests that interferon (IFN) is involved in the human anti-DEN virus response, we tested mice deficient in their IFN functions as potential models. Intraperitoneally administered mouse-adapted DEN 2 virus was uniformly lethal in AG129 mice (which lack alpha/beta IFN and gamma IFN receptor genes), regardless of age. Immunized m...

  13. Chronic Myeloid Leukemia (CML) Mouse Model in Translational Research.

    Science.gov (United States)

    Peng, Cong; Li, Shaoguang

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of granulocytic cells without the loss of their capability to differentiate. CML is a clonal disease, originated at the level of Hematopoietic Stem Cells with the Philadelphia chromosome resulting from a reciprocal translocation between the chromosomes 9 and 22t(9;22)-(q34;q11). This translocation produces a fusion gene known as BCR-ABL which acquires uncontrolled tyrosine kinase activity, constantly turning on its downstream signaling molecules/pathways, and promoting proliferation of leukemia cell through anti-apoptosis and acquisition of additional mutations. To evaluate the role of each critical downstream signaling molecule of BCR-ABL and test therapeutic drugs in vivo, it is important to use physiological mouse disease models. Here, we describe a mouse model of CML induced by BCR-ABL retrovirus (MSCV-BCR-ABL-GFP; MIG-BCR-ABL) and how to use this model in translational research.Moreover, to expand the application of this retrovirus induced CML model in a lot of conditional knockout mouse strain, we modified this vector to a triple gene coexpression vector in which we can co-express BCR-ABL, GFP, and a third gene which will be tested in different systems. To apply this triple gene system in conditional gene knockout strains, we can validate the CML development in the knockout mice and trace the leukemia cell following the GFP marker. In this protocol, we also describe how we utilize this triple gene system to prove the function of Pten as a tumor suppressor in leukemogenesis. Overall, this triple gene system expands our research spectrum in current conditional gene knockout strains and benefits our CML translational research. PMID:27150093

  14. Mouse models for genes involved in impaired spermatogenesis.

    Science.gov (United States)

    O'Bryan, M K; de Kretser, D

    2006-02-01

    Since the introduction of molecular biology and gene ablation technologies there have been substantial advances in our understanding of how sperm are made and fertilization occurs. There have been at least 150 different models of specifically altered gene function produced that have resulted in male infertility spanning virtually all aspects of the spermatogenic, sperm maturation and fertilization processes. While each has, or potentially will reveal, novel aspects of these processes, there is still much of which we have little knowledge. The current review is by no means a comprehensive list of these mouse models, rather it gives an overview of the potential for such models which up to this point have generally been 'knockouts'; it presents alternative strategies for the production of new models and emphasizes the importance of thorough phenotypic analysis in order to extract a maximum amount of information from each model.

  15. Prolonged gabapentin analgesia in an experimental mouse model of fibromyalgia

    Directory of Open Access Journals (Sweden)

    Ueda Hiroshi

    2008-11-01

    Full Text Available Abstract In a new mouse model for generalized pain syndrome, including fibromyalgia, which used intermittent cold stress (ICS, bilateral allodynia in the hindpaw was observed that lasted more than 12 days; thermal hyperalgesia lasted 15 days. During constant cold stress (CCS, mice showed only a transient allodynia. A female prevalence in ICS-induced allodynia was observed in gonadectomized but not in gonad intact mice. Systemic gabapentin showed complete anti-allodynic effects in the ICS model at the one-tenth dose for injury-induced neuropathic pain model, and central gabapentin showed long-lasting analgesia for 4 days in ICS, but not the injury model. These results suggest that the ICS model is useful for the study of generalized pain syndrome.

  16. Recent advances in mouse models of obesityandnonalcoholic steatohepatitis-associatedhepatocarcinogenesis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth mostcommon cancer, and obesity has been establishedas a risk factor for HCC development. Nonalcoholicsteatohepatitis (NASH) is apparently the key linkbetween obesity and hepatocarcinogenesis, and obesityalso accelerates HCC development synergistically withother risk factors, such as hepatitis virus infectionand alcohol consumption. As an explanation for thepathogenesis of NASH, the so-called "two-hit" theoryhas been widely accepted, but recently, a better model,the so-called "multiple-hits hypothesis" was proposed,which states that many disease-promoting factors mayoccur in parallel, rather than consecutively. However,the overall mechanism remains largely unknown. Variouscell-cell and organ-organ interactions are involved inthe pathogenesis of NASH, and thus appropriate in vivodisease models are essential for a deeper understanding.However, replicating the full spectrum of human NASHhas been difficult, as NASH involves obesity, insulinresistance, steatohepatitis, fibrosis, and ultimately HCC,and the lack of an appropriate mouse model has beena considerable barrier to determining the missing linksamong obesity, NASH, and HCC. In recent years, severalinnovative mouse models presenting obesity- and NASHassociatedHCC have been established by modifieddiets, chemotoxic agents, genetic manipulation, or acombination of these factors, shedding some light onthis complex network and providing new therapeuticstrategies. Thus, in this paper, I review the mousemodels of obesity- and NASH-associated HCC, especiallyfocusing on recent advances and their clinical relevance.

  17. 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.

  18. A new mouse model of metabolic syndrome and associated complications

    Science.gov (United States)

    Wang, Yun; Zheng, Yue; Nishina, Patsy M; Naggert, Jürgen K.

    2010-01-01

    Metabolic Syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy. A backcross was used to genetically map the Nmf15 locus. Mice were examined in the CLAMS™ animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Hypothalamic LepR, SOCS1 and STAT3 phosphorylation were examined. Cardiac function was assessed by Echo- and Electro Cardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity. The Nmf15 locus mapped to distal mouse chromosome 5 with a LOD score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly elevated in pre-obese Nmf15 mice at 8 weeks of age and an attenuated STAT3 phosphorylation in the hypothalamus suggests a primary leptin resistance. Adipose tissue from Nmf15 mice showed a remarkable degree of inflammation and macrophage infiltration as indicated by expression of the F4/80 marker and increased phosphorylation of JNK1/2. Lipidosis was observed in tubular epithelial cells and glomeruli of the kidney. Nmf15 mice demonstrate both histological and pathophysiological evidence of cardiomyopathy. The Nmf15 mouse model provides a new entry point into pathways mediating leptin resistance and obesity. It is one of few models that combine many aspects of metabolic syndrome and can be useful for testing new therapeutic approaches for combating obesity complications, particularly cardiomyopathy. PMID:19398498

  19. Cardiac manifestations in the mouse model of mucopolysaccharidosis I

    OpenAIRE

    Jordan, Maria C.; Zheng, Yi; Ryazantsev, Sergey; Rozengurt, Nora; Roos, Kenneth P.; Neufeld, Elizabeth F.

    2005-01-01

    Mucopolysaccharidosis I (MPS I, α-l-iduronidase deficiency disease) is a heritable lysosomal storage disorder involving multiple organs, including the heart. Malfunction of the heart is also a major manifestation in the mouse model of MPS I, progressing in severity from 6 to 10 months (of a one-year life span). In comparisons of MPS I with wild type mice, the heart was found enlarged, with thickened septal and posterior walls, primarily because of infiltration of the muscle by storage-laden c...

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

    Directory of Open Access Journals (Sweden)

    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 Stargardt 3 Dominant Macular Degeneration.

    Science.gov (United States)

    Barabas, Peter; Gorusupudi, Aruna; Bernstein, Paul S; Krizaj, David

    2016-01-01

    Stargardt type 3 macular degeneration is dependent on a dominant defect in a single gene, ELOVL4 (elongase of very long chain fatty acids 4). The encoded enzyme, ELOVL4, is required for the synthesis of very long chain polyunsaturated fatty acids (VLC-PUFAs), a rare class of > C24 lipids. In vitro expression studies suggest that mutated ELOVL4(STGD3) proteins fold improperly, resulting in ER stress and formation of cytosolic aggresomes of wild type and mutant ELOVL4. Although a number of mouse models have been developed to determine whether photoreceptor cell loss in STGD3 results from depletion of VLC-PUFAs, aggresome-dependent cell stress or a combination of these two factors, none of these models adequately recapitulates the disease phenotype in humans. Thus, the precise molecular mechanism by which ELOVL4 mutation causes photoreceptor degeneration in mice and in human patients remains to be characterized. This mini review compares and evaluates current STGD3 mouse models and determines what conclusions can be drawn from past work. PMID:26427404

  2. A new humanized mouse model for alopecia areata.

    Science.gov (United States)

    Gilhar, Amos; Keren, Aviad; Paus, Ralf

    2013-12-01

    Although alopecia areata (AA) is not life threatening, it may lead to severe psychological disturbances, reducing the quality of life in all ages. Thus, a new animal model is needed for shedding more light onto the pathogenesis of this cell-mediated, organ-specific autoimmune disease to identify more effective therapeutic strategies. Recently, we succeeded in developing a new humanized mouse model of AA, which includes transplantation of healthy human scalp skin obtained from normal volunteers on to severe-combined immunodeficient mice. This is followed by intradermal injection of either autologous or allogeneic peripheral blood mononuclear cells, which had been cultured with high dose of IL-2 and enriched for natural killer group 2D-positive (NKG2D+) and CD56+ cells. This protocol leads to rapid and predictable development of focal hair loss, with all the characteristic clinical, histological, and immunohistochemical features of AA. This humanized mouse AA model underscores the functional importance of NKG2D+ and CD56+ cells in AA pathogenesis and promises to be instrumental for identifying novel AA treatment strategies. PMID:24326548

  3. Choice of mouse strain influences the outcome in a mouse model of chemical-induced asthma.

    Directory of Open Access Journals (Sweden)

    Vanessa De Vooght

    Full Text Available BACKGROUND: The development of occupational asthma is the result of interactions between environmental factors and individual susceptibility. We assessed how our model of chemical-induced asthma is influenced by using different mouse strains. METHODOLOGY/PRINCIPAL FINDINGS: On days 1 and 8, male mice of 7 different strains (BALB/c, BP/2, A/J, C57Bl/6, DBA/2, CBA and AKR were dermally treated with toluene-2,4-diisocyanate (TDI (0.3% or vehicle (acetone/olive oil, AOO, 2:3 on each ear (20 microl. On day 15, they received an oropharyngeal instillation of TDI (0.01% or AOO (1:4. Airway reactivity to methacholine, total and differential cell counts in bronchoalveolar lavage (BAL and total serum IgE and IgG(2a levels were measured. Lymphocyte subpopulations in auricular lymph nodes and in vitro release of cytokines by ConA stimulated lymphocytes were assessed. In TDI-sensitized and challenged mice, airway hyper-reactivity was only observed in BALB/c, BP/2, A/J and AKR mice; airway inflammation was most pronounced in BALB/c mice; numbers of T-helper (CD4(+, T-activated (CD4(+CD25(+, T-cytotoxic (CD8(+ and B- lymphocytes (CD19(+ were increased in the auricular lymph nodes of BALB/c, BP/2, A/J and CBA mice; elevated concentrations of IL-4, IL-10, IL-13 and IFN-gamma were detected in supernatant of lymphocytes from BALB/c, BP/2, A/J, C57Bl/6 and CBA mice cultured with concanavaline A, along with an increase in total serum IgE. CONCLUSION: The used mouse strain has considerable and variable impacts on different aspects of the asthma phenotype. The human phenotypical characteristics of chemically-induced occupational asthma were best reproduced in Th2-biased mice and in particular in BALB/c mice.

  4. 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

  5. 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...

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

    Directory of Open Access Journals (Sweden)

    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.

  7. MicroRNAs in mouse models of lymphoid malignancies

    Directory of Open Access Journals (Sweden)

    Nicola A. O. Zanesi

    2010-05-01

    Full Text Available The discovery of microRNAs (miRNAs has revealed a new layer of gene expression regulation that affects many normal and pathologic biological systems. Among the malignancies affected by the dysregulation of miRNAs there are cancers of lymphoid origin, in which miRNAs are thought to have tumor suppressive or tumor promoting activities, depending on the nature of their specific targets. In the last 4-5 years, the experimental field that provided the deepest insights into the in vivo biology of miRNAs is that of mouse modeling in which transgenic and knockout animals mimic, respectively, over-expression or down-regulation of specific miRNAs involved in human leukemia/lymphoma. This review discusses recent advances in our understanding of lymphoid malignancies based on the natural and engineered mouse models of three different miRNAs, miR-15a/16-1 cluster, miR-155, and miR-17-92 cluster.

  8. 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. PMID:16523244

  9. Regression of retinopathy by squalamine in a mouse model.

    Science.gov (United States)

    Higgins, Rosemary D; Yan, Yun; Geng, Yixun; Zasloff, Michael; Williams, Jon I

    2004-07-01

    The goal of this study was to determine whether an antiangiogenic agent, squalamine, given late during the evolution of oxygen-induced retinopathy (OIR) in the mouse, could improve retinal neovascularization. OIR was induced in neonatal C57BL6 mice and the neonates were treated s.c. with squalamine doses begun at various times after OIR induction. A system of retinal whole mounts and assessment of neovascular nuclei extending beyond the inner limiting membrane from animals reared under room air or OIR conditions and killed periodically from d 12 to 21 were used to assess retinopathy in squalamine-treated and untreated animals. OIR evolved after 75% oxygen exposure in neonatal mice with florid retinal neovascularization developing by d 14. Squalamine (single dose, 25 mg/kg s.c.) given on d 15 or 16, but not d 17, substantially improved retinal neovascularization in the mouse model of OIR. There was improvement seen in the degree of blood vessel tuft formation, blood vessel tortuosity, and central vasoconstriction with squalamine treatment at d 15 or 16. Single-dose squalamine at d 12 was effective at reducing subsequent development of retinal neovascularization at doses as low as 1 mg/kg. Squalamine is a very active inhibitor of OIR in mouse neonates at doses as low as 1 mg/kg given once. Further, squalamine given late in the course of OIR improves retinopathy by inducing regression of retinal neovessels and abrogating invasion of new vessels beyond the inner-limiting membrane of the retina. PMID:15128931

  10. Dysregulation of bile acid homeostasis in parenteral nutrition mouse model.

    Science.gov (United States)

    Zhan, Le; Yang, Ill; Kong, Bo; Shen, Jianliang; Gorczyca, Ludwik; Memon, Naureen; Buckley, Brian T; Guo, Grace L

    2016-01-15

    Long-term parenteral nutrition (PN) administration can lead to PN-associated liver diseases (PNALD). Although multiple risk factors have been identified for PNALD, to date, the roles of bile acids (BAs) and the pathways involved in BA homeostasis in the development and progression of PNALD are still unclear. We have established a mouse PN model with IV infusion of PN solution containing soybean oil-based lipid emulsion (SOLE). Our results showed that PN altered the expression of genes involved in a variety of liver functions at the mRNA levels. PN increased liver gene expression of Cyp7a1 and markedly decreased that of Cyp8b1, Cyp7b1, Bsep, and Shp. CYP7A1 and CYP8B1 are important for synthesizing the total amount of BAs and regulating the hydrophobicity of BAs, respectively. Consistently, both the levels and the percentages of primary BAs as well as total non-12α-OH BAs increased significantly in the serum of PN mice compared with saline controls, whereas liver BA profiles were largely similar. The expression of several key liver-X receptor-α (LXRα) target genes involved in lipid synthesis was also increased in PN mouse livers. Retinoid acid-related orphan receptor-α (RORα) has been shown to induce the expression of Cyp8b1 and Cyp7b1, as well as to suppress LXRα function. Western blot showed significantly reduced nuclear migration of RORα protein in PN mouse livers. This study shows that continuous PN infusion with SOLE in mice leads to dysregulation of BA homeostasis. Alterations of liver RORα signaling in PN mice may be one of the mechanisms implicated in the pathogenesis of PNALD. PMID:26564717

  11. 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.

  12. 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.

  13. 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.

  14. Effect of exercise on retrograde transport in a mouse model of amyotrophic lateral sclerosis

    OpenAIRE

    Whitney, Darryl Campbell

    2007-01-01

    The potential for exercise to improve function and delay disease progression in a mouse model of amyotrophic lateral sclerosis (ALS) has been examined in some detail. Recent studies have shown that retrograde transport is diminished throughout disease progression in this mouse model. The finding that exercise plus viral delivery of IGF-1 significantly improves lifespan of the G93A transgenic mouse highlights the need to investigate the mechanisms by which exercise may alter factors associated...

  15. A Neonatal Mouse Spinal Cord Compression Injury Model.

    Science.gov (United States)

    Züchner, Mark; Glover, Joel C; Boulland, Jean-Luc

    2016-01-01

    Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal cord. A major current area of research is focused on the mechanisms of adaptive plasticity that underlie spontaneous or induced functional recovery following SCI. Spontaneous functional recovery is reported to be greater early in life, raising interesting questions about how adaptive plasticity changes as the spinal cord develops. To facilitate investigation of this dynamic, we have developed a SCI model in the neonatal mouse. The model has relevance for pediatric SCI, which is too little studied. Because neural plasticity in the adult involves some of the same mechanisms as neural plasticity in early life(1), this model may potentially have some relevance also for adult SCI. Here we describe the entire procedure for generating a reproducible spinal cord compression (SCC) injury in the neonatal mouse as early as postnatal (P) day 1. SCC is achieved by performing a laminectomy at a given spinal level (here described at thoracic levels 9-11) and then using a modified Yasargil aneurysm mini-clip to rapidly compress and decompress the spinal cord. As previously described, the injured neonatal mice can be tested for behavioral deficits or sacrificed for ex vivo physiological analysis of synaptic connectivity using electrophysiological and high-throughput optical recording techniques(1). Earlier and ongoing studies using behavioral and physiological assessment have demonstrated a dramatic, acute impairment of hindlimb motility followed by a complete functional recovery within 2 weeks, and the first evidence of changes in functional circuitry at the level of identified descending synaptic connections(1). PMID:27078037

  16. Quercetin inhibits inflammatory bone resorption in a mouse periodontitis model.

    Science.gov (United States)

    Napimoga, Marcelo H; Clemente-Napimoga, Juliana T; Macedo, Cristina G; Freitas, Fabiana F; Stipp, Rafael N; Pinho-Ribeiro, Felipe A; Casagrande, Rubia; Verri, Waldiceu A

    2013-12-27

    Periodontitis is a disease that leads to bone destruction and represents the main cause of tooth loss in adults. The development of aggressive periodontitis has been associated with increased inflammatory response that is induced by the presence of a subgingival biofilm containing Aggregatibacter actinomycetemcomitans. The flavonoid quercetin (1) is widespread in vegetables and fruits and exhibits many biological properties for possible medical and clinical applications such as its anti-inflamatory and antioxidant effects. Thus, in the present study, the properties of 1 have been evaluated in bone loss and inflammation using a mouse periodontitis model induced by A. actinomycetemcomitans infection. Subcutaneous treatment with 1 reduced A. actinomycetemcomitans-induced bone loss and IL-1β, TNF-α, IL-17, RANKL, and ICAM-1 production in the gingival tissue without affecting bacterial counts. These results demonstrated that quercetin exhibits protective effects in A. actinomycetemcomitans-induced periodontitis in mice by modulating cytokine and ICAM-1 production.

  17. Transgenerational transmission of hyperactivity in a mouse model of ADHD.

    Science.gov (United States)

    Zhu, Jinmin; Lee, Kevin P; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

    2014-02-19

    Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder affecting children and adults. Genetic and environmental factors are associated with the etiology of ADHD. Among the environmental factors, exposure of the developing brain to nicotine is considered a major risk factor. Recent evidence suggests that environmental influences on the brain and behavior may be transmitted from one generation to the next. We used a prenatal nicotine exposure (PNE) mouse model of ADHD to test the hypothesis that PNE-induced hyperactivity, a proxy for human ADHD phenotype, is transmitted from one generation to the next. Our data reveal transgenerational transmission of PNE-induced hyperactivity in mice via the maternal but not the paternal line of descent. We suggest that transgenerational transmission is a plausible mechanism for propagation of environmentally induced ADHD phenotypes in the population. PMID:24553919

  18. 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.

  19. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: Consensus report and recommendations

    NARCIS (Netherlands)

    R.H. Hruban; N.V. Adsay; J. Albores-Saavedra; M.R. Anver; A.V. Biankin; G.P. Boivin; E.E. Furth; T. Furukawa; A. Klein; D.S. Klimstra; G. Kloppel; G.Y. Lauwers; D.S. Longnecker; J. Luttges; A. Maitra; G.J.A. Offerhaus; L. Perez-Gallego; M. Redston; D.A. Tuveson

    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 Na

  20. 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.

  1. 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.

  2. Automatic Segmentation Framework of Building Anatomical Mouse Model for Bioluminescence Tomography

    OpenAIRE

    Abdullah Alali

    2013-01-01

    Bioluminescence tomography is known as a highly ill-posed inverse problem. To improve the reconstruction performance by introducing anatomical structures as a priori knowledge, an automatic segmentation framework has been proposed in this paper to extract the mouse whole-body organs and tissues, which enables to build up a heterogeneous mouse model for reconstruction of bioluminescence tomography. Finally, an in vivo mouse experiment has been conducted to evaluate this framework by using an X...

  3. A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells

    OpenAIRE

    Garabedian, Emily M.; Humphrey, Peter A.; Jeffrey I Gordon

    1998-01-01

    A transgenic mouse model of metastatic prostate cancer has been developed that is 100% penetrant in multiple pedigrees. Nucleotides −6500 to +34 of the mouse cryptdin-2 gene were used to direct expression of simian virus 40 T antigen to a subset of neuroendocrine cells in all lobes of the FVB/N mouse prostate. Transgene expression is initiated between 7 and 8 weeks of age and leads to development of prostatic intraepithelial neoplasia within a week. Prostatic intraepithelial neoplasia progres...

  4. 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.

  5. Photodynamic therapy of oral Candida infection in a mouse model.

    Science.gov (United States)

    Freire, Fernanda; Ferraresi, Cleber; Jorge, Antonio Olavo C; Hamblin, Michael R

    2016-06-01

    Species of the fungal genus Candida, can cause oral candidiasis especially in immunosuppressed patients. Many studies have investigated the use of photodynamic therapy (PDT) to kill fungi in vitro, but this approach has seldom been reported in animal models of infection. This study investigated the effects of PDT on Candida albicans as biofilms grown in vitro and also in an immunosuppressed mouse model of oral candidiasis infection. We used a luciferase-expressing strain that allowed non-invasive monitoring of the infection by bioluminescence imaging. The phenothiazinium salts, methylene blue (MB) and new methylene blue (NMB) were used as photosensitizers (PS), combined or not with potassium iodide (KI), and red laser (660nm) at four different light doses (10J, 20J, 40J and 60J). The best in vitro log reduction of CFU/ml on biofilm grown cells was: MB plus KI with 40J (2.31 log; p<0.001); and NMB without KI with 60J (1.77 log; p<0.001). These conditions were chosen for treating the in vivo model of oral Candida infection. After 5days of treatment the disease was practically eradicated, especially using MB plus KI with 40J. This study suggests that KI can potentiate PDT of fungal infection using MB (but not NMB) and could be a promising new approach for the treatment of oral candidiasis.

  6. Photodynamic therapy of oral Candida infection in a mouse model.

    Science.gov (United States)

    Freire, Fernanda; Ferraresi, Cleber; Jorge, Antonio Olavo C; Hamblin, Michael R

    2016-06-01

    Species of the fungal genus Candida, can cause oral candidiasis especially in immunosuppressed patients. Many studies have investigated the use of photodynamic therapy (PDT) to kill fungi in vitro, but this approach has seldom been reported in animal models of infection. This study investigated the effects of PDT on Candida albicans as biofilms grown in vitro and also in an immunosuppressed mouse model of oral candidiasis infection. We used a luciferase-expressing strain that allowed non-invasive monitoring of the infection by bioluminescence imaging. The phenothiazinium salts, methylene blue (MB) and new methylene blue (NMB) were used as photosensitizers (PS), combined or not with potassium iodide (KI), and red laser (660nm) at four different light doses (10J, 20J, 40J and 60J). The best in vitro log reduction of CFU/ml on biofilm grown cells was: MB plus KI with 40J (2.31 log; p<0.001); and NMB without KI with 60J (1.77 log; p<0.001). These conditions were chosen for treating the in vivo model of oral Candida infection. After 5days of treatment the disease was practically eradicated, especially using MB plus KI with 40J. This study suggests that KI can potentiate PDT of fungal infection using MB (but not NMB) and could be a promising new approach for the treatment of oral candidiasis. PMID:27074245

  7. A mouse model for HBV immunotolerance and immunotherapy.

    Science.gov (United States)

    Yang, Dan; Liu, Longchao; Zhu, Danming; Peng, Hua; Su, Lishan; Fu, Yang-Xin; Zhang, Liguo

    2014-01-01

    Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/HBV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism(s) of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections. PMID:24076617

  8. Introducing Human APOE into Aβ Transgenic Mouse Models

    Directory of Open Access Journals (Sweden)

    Leon M. Tai

    2011-01-01

    Full Text Available Apolipoprotein E (apoE and apoE/amyloid-β (Aβ transgenic (Tg mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type, apoE−/− mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for Aβ-independent apoE effects on neurodegeneration. To determine the effects of apoE on Aβ-induced neuropathology, apoE−/− mice were crossed with Aβ-Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice with apoE−/−/Aβ-Tg mice further delayed plaque deposition, which eventually developed in apoE4/Aβ-Tg mice prior to apoE3/Aβ-Tg. One approach to address hAPOE-induced temporal delay in Aβ pathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with Aβ-Tg mice that have rapid-onset Aβ pathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/Aβ-Tg mice. Thus, tractable models for human-apoE/Aβ-Tg mice continue to evolve.

  9. Debridement increases survival in a mouse model of subcutaneous anthrax.

    Directory of Open Access Journals (Sweden)

    Zachary P Weiner

    Full Text Available Anthrax is caused by infection with Bacillus anthracis, a spore-forming gram-positive bacterium. A major virulence factor for B. anthracis is an immunomodulatory tripartite exotoxin that has been reported to alter immune cell chemotaxis and activation. It has been proposed that B. anthracis infections initiate through entry of spores into the regional draining lymph nodes where they germinate, grow, and disseminate systemically via the efferent lymphatics. If this model holds true, it would be predicted that surgical removal of infected tissues, debridement, would have little effect on the systemic dissemination of bacteria. This model was tested through the development of a mouse debridement model. It was found that removal of the site of subcutaneous infection in the ear increased the likelihood of survival and reduced the quantity of spores in the draining cervical lymph nodes (cLN. At the time of debridement 12 hours post-injection measurable levels of exotoxins were present in the ear, cLN, and serum, yet leukocytes within the cLN were activated; countering the concept that exotoxins inhibit the early inflammatory response to promote bacterial growth. We conclude that the initial entry of spores into the draining lymph node of cutaneous infections alone is not sufficient to cause systemic disease and that debridement should be considered as an adjunct to antibiotic therapy.

  10. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

    Science.gov (United States)

    Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

    2015-07-15

    Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path

  11. Single-Dose Radiation-Induced Oral Mucositis Mouse Model

    Science.gov (United States)

    Maria, Osama Muhammad; Syme, Alasdair; Eliopoulos, Nicoletta; Muanza, Thierry

    2016-01-01

    The generation of a self-resolved radiation-induced oral mucositis (RIOM) mouse model using the highest possibly tolerable single ionizing radiation (RT) dose was needed in order to study RIOM management solutions. We used 10-week-old male BALB/c mice with average weight of 23 g for model production. Mice were treated with an orthovoltage X-ray irradiator to induce the RIOM ulceration at the intermolar eminence of the animal tongue. General anesthesia was injected intraperitoneally for proper animal immobilization during the procedure. Ten days after irradiation, a single RT dose of 10, 15, 18, 20, and 25 Gy generated a RIOM ulcer at the intermolar eminence (posterior upper tongue surface) with mean ulcer floor (posterior epithelium) heights of 190, 150, 25, 10, and 10 μm, respectively, compared to 200 μm in non-irradiated animals. The mean RIOM ulcer size % of the total epithelialized upper surface of the animal tongue was RT dose dependent. At day 10, the ulcer size % was 2, 5, 27, and 31% for 15, 18, 20, and 25 Gy RT, respectively. The mean relative surface area of the total epithelialized upper surface of the tongue was RT dose dependent, since it was significantly decreased to 97, 95, 88, and 38% with 15, 18, 20, and 25 Gy doses, respectively, at day 10 after RT. Subcutaneous injection of 1 mL of 0.9% saline/6 h for 24 h yielded a 100% survival only with 18 Gy self-resolved RIOM, which had 5.6 ± 0.3 days ulcer duration. In conclusion, we have generated a 100% survival self-resolved single-dose RIOM male mouse model with long enough duration for application in RIOM management research. Oral mucositis ulceration was radiation dose dependent. Sufficient hydration of animals after radiation exposure significantly improved their survival. PMID:27446800

  12. 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.

  13. Breathing abnormalities in a female mouse model of Rett syndrome.

    Science.gov (United States)

    Johnson, Christopher M; Cui, Ningren; Zhong, Weiwei; Oginsky, Max F; Jiang, Chun

    2015-09-01

    Rett syndrome (RTT) is a female neurodevelopmental disease with breathing abnormalities. To understand whether breathing defects occur in the early lives of a group of female Mecp2(+/-) mice, a mouse model of RTT, and what percentage of mice shows RTT-like breathing abnormality, breathing activity was measured by plethysmography in conscious mice. Breathing frequency variation and central apnea in a group of Mecp2(+/-) females displayed a distribution pattern similar to Mecp2(-/Y) males, while the rest resembled the wild-type mice. Similar results were obtained using the k-mean clustering statistics analysis. With two independent methods, about 20% of female Mecp2(+/-) mice showed RTT-like breathing abnormalities that began as early as 3 weeks of age in the Mecp2(+/-) mice, and were suppressed with 3% CO2. The finding that only a small proportion of Mecp2(+/-) mice develops RTT-like breathing abnormalities suggests incomplete allele inactivation in the RTT-model Mecp2(+/-) mice.

  14. Cardiac Dysfunction in the BACHD Mouse Model of Huntington's Disease.

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    Analyne M Schroeder

    Full Text Available While Huntington's disease (HD is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3 months of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis and ultimately apoptosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol treatment; however, the medication exacerbated fibrotic lesions in the heart. Gene expression analysis indicated a strong tilt toward apoptosis in the young mutant heart as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the large changes occurring in the cardiovascular disease, cellular metabolism, and cellular transport clusters. The BACHD model of HD exhibits a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher cardiovascular risk in HD.

  15. The tumor suppressor kinase LKB1: lessons from mouse models

    Institute of Scientific and Technical Information of China (English)

    Saara Ollila; Tomi P. M(a)kel(a)

    2011-01-01

    Mutations in the tumor suppressor gene LKB1 are important in hereditary Peutz-Jeghers syndrome,as well as in sporadic cancers including lung and cervical cancer.LKB1 is a kinase-activating Kinase,and a number of LKB1-dependent phosphorylation cascades regulate fundamental cellular and organismal processes in at least metabolism,polarity,cytoskeleton organization,and proliferation.Conditional targeting approaches are beginning to demonstrate the relevance and specificity of these signaling pathways in development and homeostasis of multiple organs.More than one of the pathways also appear to contribute to tumor growth following Lkb1 deficiencies based on a number of mouse tumor models.Lkb1-dependent activation of AMPK and subsequent inactivation of mammalian target of rapamycin signaling are implicated in several of the models,and other less well characterized pathways are also involved.Conditional targeting studies of Lkb1 also point an important role of LKB1 in epithelial-masenchymal interactions,significantly expanding knowledge on the relevance of LKB1 in human disease.

  16. Development of a Nongenetic Mouse Model of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Gilbert

    2011-01-01

    Full Text Available Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D. The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1 low-fat diet (LFD; low-fat control; LFC, (2 LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ injection, (3, (4, (5, (6 LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7 high-fat diet (HFD, (8 HFD with 1 STZ injection, (9, (10, (11, (12 HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

  17. Reproductive Phenotypes of Mouse Models Illuminate Human Infertility

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    Adelfalk C

    2011-01-01

    Full Text Available Infertility represents a significant health problem in industrialized nations because reproductive activity is increasingly delayed and couples face a risk of impaired fetal health at advanced maternal age (35 years. Furthermore, approx. fifteen percent of couples have difficulties to conceive within a year of unprotected intercourse. Reduced reproductive success often relates to a defective meiotic process that would normally lead to formation of ova and sperm. The understanding of the mechanisms of meiosis and fertility has largely benefitted from knockout and transgenic mouse models that display a fertility phenotype. Using information from meiosis-deficient mice has impacted on the diagnosis of infertility of unknown origin of human patients. In this paper we discuss insights gained in the etiology of infertility by looking at murine genetic models with a reproductive phenotype due to disruptions in genes acting during meiotic prophase. We focus on genes that are important for recombinational DNA repair, meiotic chromosome structure and reproductive aging and will compare these phenotypes to human conditions with reproductive impairmen

  18. Lung Cancer Signatures in Plasma Based on Proteome Profiling of Mouse Tumor Models

    OpenAIRE

    Taguchi, Ayumu; Politi, Katerina; Pitteri, Sharon J.; Lockwood, William W; Faça, Vitor M.; Kelly-Spratt, Karen; Wong, Chee-Hong; Zhang, Qing; Chin, Alice; Park, Kwon-Sik; Goodman, Gary; Gazdar, Adi F.; Sage, Julien; Dinulescu, Daniela M.; Kucherlapati, Raju

    2011-01-01

    We investigated the potential of in-depth quantitative proteomics to reveal plasma protein signatures that reflect lung tumor biology. We compared plasma protein profiles of four mouse models of lung cancer with profiles of models of pancreatic, ovarian, colon, prostate, and breast cancer and two models of inflammation. A protein signature for Titf1/Nkx2-1, a known lineage-survival oncogene in lung cancer, was found in plasmas of mouse models of lung adenocarcinoma. An EGFR signature was foun...

  19. Modeling Breast Tumor Development with a Humanized Mouse Model.

    Science.gov (United States)

    Arendt, Lisa M

    2016-01-01

    The tumor microenvironment plays a critical role in breast cancer growth and progression to metastasis. Here, we describe a method to examine stromal-epithelial interactions during tumor formation and progression utilizing human-derived mammary epithelial cells and breast stromal cells. This method outlines the isolation of each cell type from reduction mammoplasty tissue, the culture and genetic modification of both epithelial and stromal cells using lentiviral technology, and the method of humanizing and implantation of transformed epithelial cells into the cleared mammary fat pads of immunocompromised mice. This model system may be a useful tool to dissect signaling interactions that contribute to invasive tumor behavior and therapeutic resistance. PMID:27581027

  20. 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...

  1. Conditional Expression of Human 15-Lipoxygenase-1 in Mouse Prostate Induces Prostatic Intraepithelial Neoplasia: The FLiMP Mouse Model

    Directory of Open Access Journals (Sweden)

    Uddhav P. Kelavkar

    2006-06-01

    Full Text Available The incidence and mortality of prostate cancer (PCa vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1, which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN, and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt, FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC, and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN. In summary, targeted overexpression of h

  2. Transgenic mouse model for the formation of Hirano bodies

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    Stramiello Michael

    2011-10-01

    Full Text Available Abstract Background Hirano bodies are actin-rich cytoplasmic inclusions found predominantly in the brain in association with a variety of conditions including aging and Alzheimer's disease. The function of Hirano bodies in normal aging and in progression of disease has not been extensively investigated due to a lack of experimental model systems. We have developed a transgenic mouse model by expression of a gain-of-function actin cross-linking protein mutant. Results We used the Cre/loxP system to permit tissue specific expression of Hirano bodies, and employed the murine Thy 1 promoter to drive expression of Cre recombinase in the brain. Hirano bodies were observed in the cerebral cortex and hippocampus of homozygous double transgenic 6 month old mice containing Cre. The Hirano bodies were eosinophilic rods, and also exhibited the paracrystalline F-actin filament organization that is characteristic of these inclusions. Mice with Hirano bodies appear healthy and fertile, but exhibited some alterations in both short-term and long-term synaptic plasticity, including paired-pulse depression rather than facilitation, and decreased magnitude of early LTP. Conclusions Hirano bodies are not lethal and appear to have little or no effect on histology and tissue organization. Hirano bodies do modulate synaptic plasticity and exert clearly discernable effects on LTP and paired-pulse paradigms. This model system will allow us to investigate the impact of Hirano bodies in vivo, the pathways for formation and degradation of Hirano bodies, and whether Hirano bodies promote or modulate development of pathology and disease progression.

  3. Assessing functional performance in the mdx mouse model.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; van Putten, Maaike

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential pharmaceutical compounds and gene therapy approaches have progressed into clinical trials. With improvement in muscle function being the most important end point in these trials, a lot of emphasis has been placed on setting up reliable, reproducible, and easy to perform functional tests to pre clinically assess muscle function, strength, condition, and coordination in the mdx mouse model for DMD. Both invasive and noninvasive tests are available. Tests that do not exacerbate the disease can be used to determine the natural history of the disease and the effects of therapeutic interventions (e.g. forelimb grip strength test, two different hanging tests using either a wire or a grid and rotarod running). Alternatively, forced treadmill running can be used to enhance disease progression and/or assess protective effects of therapeutic interventions on disease pathology. We here describe how to perform these most commonly used functional tests in a reliable and reproducible manner. Using these protocols based on standard operating procedures enables comparison of data between different laboratories. PMID:24747372

  4. 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.

  5. Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

    Science.gov (United States)

    Vyazunova, Irina; Maklakova, Vilena I.; Berman, Samuel; De, Ishani; Steffen, Megan D.; Hong, Won; Lincoln, Hayley; Morrissy, A. Sorana; Taylor, Michael D.; Akagi, Keiko; Brennan, Cameron W.; Rodriguez, Fausto J.; Collier, Lara S.

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma. PMID:25423036

  6. Mouse model for ROS1-rearranged lung cancer.

    Directory of Open Access Journals (Sweden)

    Yasuhito Arai

    Full Text Available Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC. However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.

  7. Mouse Model for ROS1-Rearranged Lung Cancer

    Science.gov (United States)

    Takahashi, Hiroyuki; Nakamura, Hiromi; Hama, Natsuko; Kohno, Takashi; Tsuta, Koji; Yoshida, Akihiko; Asamura, Hisao; Mutoh, Michihiro; Hosoda, Fumie; Tsuda, Hitoshi; Shibata, Tatsuhiro

    2013-01-01

    Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22–q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer. PMID:23418494

  8. Mouse Models of Type 2 Diabetes Mellitus in Drug Discovery.

    Science.gov (United States)

    Baribault, Helene

    2016-01-01

    Type 2 diabetes is a fast-growing epidemic in industrialized countries, associated with obesity, lack of physical exercise, aging, family history, and ethnic background. Diagnostic criteria are elevated fasting or postprandial blood glucose levels, a consequence of insulin resistance. Early intervention can help patients to revert the progression of the disease together with lifestyle changes or monotherapy. Systemic glucose toxicity can have devastating effects leading to pancreatic beta cell failure, blindness, nephropathy, and neuropathy, progressing to limb ulceration or even amputation. Existing treatments have numerous side effects and demonstrate variability in individual patient responsiveness. However, several emerging areas of discovery research are showing promises with the development of novel classes of antidiabetic drugs.The mouse has proven to be a reliable model for discovering and validating new treatments for type 2 diabetes mellitus. We review here commonly used methods to measure endpoints relevant to glucose metabolism which show good translatability to the diagnostic of type 2 diabetes in humans: baseline fasting glucose and insulin, glucose tolerance test, insulin sensitivity index, and body type composition. Improvements on these clinical values are essential for the progression of a novel potential therapeutic molecule through a preclinical and clinical pipeline.

  9. Enzyme replacement therapy in a mouse model of aspartylglycosaminuria.

    Science.gov (United States)

    Dunder, U; Kaartinen, V; Valtonen, P; Väänänen, E; Kosma, V M; Heisterkamp, N; Groffen, J; Mononen, I

    2000-02-01

    Aspartylglycosaminuria (AGU), the most common lysosomal disorder of glycoprotein degradation, is caused by deficient activity of glycosylasparaginase (AGA). AGA-deficient mice share most of the clinical, biochemical and histopathologic characteristics of human AGU disease. In the current study, recombinant human AGA administered i.v. to adult AGU mice disappeared from the systemic circulation of the animals in two phases predominantly into non-neuronal tissues, which were rapidly cleared from storage compound aspartylglucosamine. Even a single AGA injection reduced the amount of aspartylglucosamine in the liver and spleen of AGU mice by 90% and 80%, respectively. Quantitative biochemical analyses along with histological and immunohistochemical studies demonstrated that the pathophysiologic characteristics of AGU were effectively corrected in non-neuronal tissues of AGU mice during 2 wk of AGA therapy. At the same time, AGA activity increased to 10% of that in normal brain tissue and the accumulation of aspartylglucosamine was reduced by 20% in total brain of the treated animals. Immunohistochemical studies suggested that the corrective enzyme was widely distributed within the brain tissue. These findings suggest that AGU may be correctable by enzyme therapy.-Dunder, U., Kaartinen, V., Valtonen, P., Väänänen, E., Kosma, V.-M., Heisterkamp, N., Groffen, J., Mononen, I. Enzyme replacement therapy in a mouse model of aspartylglycosaminuria.

  10. 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.

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

    OpenAIRE

    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 ...

  12. 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.

  13. Mouse Model for the Preclinical Study of Metastatic Disease | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The Laboratory of Cancer Biology and Genetics, National Cancer Institute seeks partners for collaborative research to co-develop a mouse model that shows preclinical therapeutic response of residual metastatic disease.

  14. Automatic Assessment of Craniofacial Growth in a Mouse Model of Crouzon Syndrome

    DEFF Research Database (Denmark)

    Thorup, Signe Strann; Larsen, Rasmus; Darvann, Tron Andre;

    2009-01-01

    BACKGROUND & PURPOSE: Crouzon syndrome is characterized by growth disturbances caused by premature craniosynostosis. A mouse model with mutation Fgfr2C342Y, equivalent to the most common Crouzon syndrome mutation (henceforth called the Crouzon mouse model), has a phenotype showing many parallels...... to the human counterpart. Quantifying growth in the Crouzon mouse model could test hypotheses of the relationship between craniosynostosis and dysmorphology, leading to better understanding of the causes of Crouzon syndrome as well as providing knowledge relevant for surgery planning. METHODS: Automatic non......-rigid volumetric image registration was applied to micro-CT scans of ten 4-week and twenty 6-week euthanized mice for growth modeling. Each age group consisted of 50% normal and 50% Crouzon mice. Four 3D mean shapes, one for each mouse-type and age group were created. Extracting a dense field of growth vectors...

  15. 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.

  16. Oxalobacter formigenes Colonization and Oxalate Dynamics in a Mouse Model.

    Science.gov (United States)

    Li, Xingsheng; Ellis, Melissa L; Knight, John

    2015-08-01

    Animal and human studies have provided compelling evidence that colonization of the intestine with Oxalobacter formigenes reduces urinary oxalate excretion and lowers the risk of forming calcium oxalate kidney stones. The mechanism providing protection appears to be related to the unique ability of O. formigenes to rely on oxalate as a major source of carbon and energy for growth. However, much is not known about the factors that influence colonization and host-bacterium interactions. We have colonized mice with O. formigenes OxCC13 and systematically investigated the impacts of diets with different levels of calcium and oxalate on O. formigenes intestinal densities and urinary and intestinal oxalate levels. Measurement of intestinal oxalate levels in mice colonized or not colonized with O. formigenes demonstrated the highly efficient degradation of soluble oxalate by O. formigenes relative to other microbiota. The ratio of calcium to oxalate in diets was important in determining colonization densities and conditions where urinary oxalate and fecal oxalate excretion were modified, and the results were consistent with those from studies we have performed with colonized and noncolonized humans. The use of low-oxalate purified diets showed that 80% of animals retained O. formigenes colonization after a 1-week dietary oxalate deprivation. Animals not colonized with O. formigenes excreted two times more oxalate in feces than they had ingested. This nondietary source of oxalate may play an important role in the survival of O. formigenes during periods of dietary oxalate deprivation. These studies suggest that the mouse will be a useful model to further characterize interactions between O. formigenes and the host and factors that impact colonization. PMID:25979889

  17. Review: The history and role of naturally occurring mouse models with Pde6b mutations

    OpenAIRE

    Han, Juanjuan; Dinculescu, Astra; Dai, Xufeng; Du, Wei; Smith, W. Clay; Pang, Jijing

    2013-01-01

    Mouse models are useful tools for developing potential therapies for human inherited retinal diseases, such as retinitis pigmentosa (RP), since more strains are being identified with the same mutant genes and phenotypes as humans with corresponding retinal degenerative diseases. Mutations in the beta subunit of the human rod phosphodiesterase (PDE6B) gene are a common cause of autosomal recessive RP (arRP). This article focuses on two well-established naturally occurring mouse models of arRP ...

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

    Directory of Open Access Journals (Sweden)

    Blake Gurfein

    2012-09-01

    Full Text Available Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, suppressed immunity, and central nervous system neuropathology. While human studies have illustrated the benefits of stress reduction, mechanistic understanding of how decreasing stress affects health, and disease progression remains unclear. Furthermore, prior animal studies have focused primarily on increasing stress, and few animal models of stress reduction have been fully developed. 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 (n=10/group: 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; Calm Exercise (Calm Ex, Calm caging with a running wheel.Calm, Cntl Ex, and Calm Ex animals exhibited significantly less corticosterone production than Cntl (Day 49: Calm, Mdiff 20.5 ng corticosterone metabolites/0.05 g feces (CM, CI95 11.7–29.4, P<0.0001; Cntl Ex, Mdiff 22.5 ng CM, CI95 13.4–31.5, P<0.0001; Calm Ex, Mdiff 21.8 CM, CI95 11.7–32.0, P=0.0003. Calm animals gained greater body mass than Cntl, although they had similar weekly energy intake. We also observed changes in body composition, spleen mass, and spleen composition. In particular, we found that Calm mice had a significantly greater proportion and absolute number of splenic CD19+ B lymphocytes when compared with Cntl (proportion: Mdiff 6.7% of splenocytes, P<0.0001; absolute number: Mdiff 9.04 × 106 cells, CI95 8.3×106–9.8×106, P<0.0001.Our data indicate that both Calm and exercise caging generated reductions in physiologic stress measures in mice and that Calm animals exhibited increases in splenocyte

  19. Application and detection of (14)c-hd in two mouse models.

    Science.gov (United States)

    Logan, Thomas P; Shutz, Michael; Schulz, Susan M; Railer, Roy; Ricketts, Karen M; Casillas, Robert P

    2002-01-01

    The CD1-haired mouse and the SKH-hairless mouse are two animal models that have been used to evaluate sulfur mustard (HD) exposure and protection in our laboratory. In a recent study we observed that a substance P inhibitor protected the haired mouse ear against an HD solution, but the same drug was not successful in protecting the hairless mouse against HD vapor. This experiment prompted us to compare HD exposures between these models. We determined the (14)C content in the skin after exposures to HD containing (14)C-HD. Rate curves were generated for applications of (1) HD in methylene chloride to the haired mouse ear; (2) HD in methylene chloride to the hairless mouse dorsal skin; and (3) saturated HD vapor to the hairless mouse dorsal skin for 6 min. The curves showed a reduction in (14)C disintegrations per min in animals euthanized 0 to 2 h postexposure. The largest percentage of decrease of (14)C content in skin occurred within 30 min of HD challenge for all exposures. An 8-mm skin-punch biopsy and a 14-mm annular skin section surrounding the region of the 8-mm skin punch were taken from the hairless mouse dorsal skin exposed to HD in methylene chloride. The ratio of the (14)C content in the 8-mm skin punch to that in the surrounding 14-mm annular skin section was 7.3, demonstrating that the HD application spreads beyond the initially biopsied site. A concentration/time value of 6.3 mug/cm(2)/min was determined by counting skin (14)C disintegrations per minute in animals euthanized immediately after exposure to saturated HD vapor. Determinations of the amount of HD showed that similar quantities of HD, 0.4 mg, were detected on each model. These results contribute to a better quantitative understanding of HD application in the haired and hairless mouse models.

  20. Live dynamic imaging and analysis of developmental cardiac defects in mouse models with optical coherence tomography

    Science.gov (United States)

    Lopez, Andrew L.; Wang, Shang; Garcia, Monica; Valladolid, Christian; Larin, Kirill V.; Larina, Irina V.

    2015-03-01

    Understanding mouse embryonic development is an invaluable resource for our interpretation of normal human embryology and congenital defects. Our research focuses on developing methods for live imaging and dynamic characterization of early embryonic development in mouse models of human diseases. Using multidisciplinary methods: optical coherence tomography (OCT), live mouse embryo manipulations and static embryo culture, molecular biology, advanced image processing and computational modeling we aim to understand developmental processes. We have developed an OCT based approach to image live early mouse embryos (E8.5 - E9.5) cultured on an imaging stage and visualize developmental events with a spatial resolution of a few micrometers (less than the size of an individual cell) and a frame rate of up to hundreds of frames per second and reconstruct cardiodynamics in 4D (3D+time). We are now using these methods to study how specific embryonic lethal mutations affect cardiac morphology and function during early development.

  1. The hGFAP-driven conditional TSPO knockout is protective in a mouse model of multiple sclerosis

    OpenAIRE

    Daniel J. Daugherty; Olga Chechneva; Florian Mayrhofer; Wenbin Deng

    2016-01-01

    The mitochondrial translocator protein (TSPO) has been implicated in CNS diseases. Here, we sought to determine the specific role of TSPO in experimental autoimmune encephalomyelitis (EAE), the most studied animal model of multiple sclerosis (MS). To fundamentally elucidate the functions of TSPO, we first developed a viable TSPO knockout mouse. A conditional TSPO knockout mouse was generated by utilizing the Cre-Lox system. We generated a TSPO floxed mouse, and then crossed this mouse with a ...

  2. Small-diameter biodegradable scaffolds for functional vascular tissue engineering in the mouse model

    OpenAIRE

    Roh, Jason D.; Nelson, Gregory N.; Brennan, Matthew P.; Mirensky, Tamar L.; Yi, Tai; Hazlett, Ty; Tellides, George; Sinusas, Albert J.; Pober, Jordan S.; Saltzman, W. Mark; Kyriakides, Themis R.; Breuer, Christopher K

    2007-01-01

    The development of neotissue in tissue engineered vascular grafts remains poorly understood. Advances in mouse genetic models have been highly informative in the study of vascular biology, but have been inaccessible to vascular tissue engineers due to technical limitations on the use of mouse recipients. To this end, we have developed a method for constructing sub-1mm internal diameter (I.D.) biodegradable scaffolds utilizing a dual cylinder chamber molding system and a hybrid polyester seala...

  3. MAGNETIC RESONANCE IMAGING AND SPECTROSCOPY IN A MOUSE MODEL OF SCHIZOPHRENIA

    OpenAIRE

    Torres, German; Hallas, Brian H.; Gross, Kenneth W.; Spernyak, Joseph A.; Horowitz, Judith M.

    2007-01-01

    Metabolic brain abnormalities, as demonstrated by 1H-magnetic resonance spectroscopy techniques, are common occurrences in adult schizophrenia. As mice share important biochemical and genomic similarities with humans, we tested whether brain metabolic abnormalities also occur in a transgenic mouse model of schizophrenia. In vivo 1H-magnetic resonance spectroscopy at 4.7 T of the chakragati mouse brain revealed abnormalities in relative levels of choline 3.20 ppm and N-acetylaspartate 2.01 ppm...

  4. PANIC-ATTAC: A Mouse Model for Inducible and Reversible β-Cell Ablation

    OpenAIRE

    Wang, Zhao V.; Mu, James; Schraw, Todd D.; Gautron, Laurent; Elmquist, Joel K.; Zhang, Bei B.; Brownlee, Michael; Scherer, Philipp E

    2008-01-01

    OBJECTIVE—Islet transplantations have been performed clinically, but their practical applications are limited. An extensive effort has been made toward the identification of pancreatic β-cell stem cells that has yielded many insights to date, yet targeted reconstitution of β-cell mass remains elusive. Here, we present a mouse model for inducible and reversible ablation of pancreatic β-cells named the PANIC-ATTAC (pancreatic islet β-cell apoptosis through targeted activation of caspase 8) mous...

  5. Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model

    OpenAIRE

    Hillegass, Jedd M; Shukla, Arti; Lathrop, Sherrill A.; MacPherson, Maximilian B; Beuschel, Stacie L; Butnor, Kelly J.; Testa, Joseph R.; Harvey I Pass; Carbone, Michele; Steele, Chad; Mossman, Brooke T.

    2010-01-01

    Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived ...

  6. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy

    OpenAIRE

    Kappen, Claudia; Kruger, Claudia; Macgowan, Jacalyn; Salbaum, J. Michael

    2010-01-01

    Pregnancies complicated by maternal diabetes have long been known to carry a higher risk for congenital malformations, such as neural tube defects. Using the FVB inbred mouse strain and the Streptozotocin-induced diabetes model, we tested whether the incidence of neural tube defects in diabetic pregnancies can be modulated by maternal diet. In a comparison of two commercial mouse diets, which are considered nutritionally replete, we found that maternal consumption of the unfavorable diet was ...

  7. Protective Effect of Arginine on Oxidative Stress in Transgenic Sickle Mouse Models

    OpenAIRE

    Dasgupta, Trisha; Hebbel, Robert P.; Kaul, Dhananjay K.

    2006-01-01

    Sickle cell disease (SCD) is characterized by reperfusion injury and chronic oxidative stress. Oxidative stress and hemolysis in SCD result in inactivation of nitric oxide (NO) and depleted arginine levels. We hypothesized that augmenting NO production by arginine supplementation will reduce oxidative stress in SCD. To this end, we measured the effect of arginine (5% in mouse chow) on NO metabolites (NOx), lipid peroxidation (LPO) and selected antioxidants in transgenic sickle mouse models. U...

  8. Type 2 diabetes model TSOD mouse is exposed to oxidative stress at young age

    OpenAIRE

    Murotomi, Kazutoshi; Umeno, Aya; Yasunaga, Mayu; Shichiri, Mototada; Ishida, Noriko; Abe, Hiroko; Yoshida, Yasukazu; Nakajima, Yoshihiro

    2014-01-01

    Tsumura Suzuki Obese Diabetes (TSOD) mouse, a model of obese type 2 diabetes, older than around 11 weeks of age develops diabetic phenotypes. Previous studies have indicated that the development of diabetes is partly due to three loci associated with body weight and glucose homeostasis. However, little is known about the initial events triggering the development of the diabetic phenotypes in TSOD mouse. Here, we investigated the alteration of diabetes-related parameters, including the levels ...

  9. Impaired Satiation and Increased Feeding Behaviour in the Triple-Transgenic Alzheimer's Disease Mouse Model

    OpenAIRE

    Adedolapo Adebakin; Jenna Bradley; Sarah Gümüsgöz; Elizabeth J Waters; Lawrence, Catherine B.

    2012-01-01

    Alzheimer's disease (AD) is associated with non-cognitive symptoms such as changes in feeding behaviour that are often characterised by an increase in appetite. Increased food intake is observed in several mouse models of AD including the triple transgenic (3×TgAD) mouse, but the mechanisms underlying this hyperphagia are unknown. We therefore examined feeding behaviour in 3×TgAD mice and tested their sensitivity to exogenous and endogenous satiety factors by assessing food intake and activat...

  10. Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

    OpenAIRE

    Katie Lidster; Samuel J Jackson; Zubair Ahmed; Peter Munro; Pete Coffey; Gavin Giovannoni; Baker, Mark D.; David Baker

    2013-01-01

    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 transge...

  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 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.

  13. Alterations in striatal synaptic transmission are consistent across genetic mouse models of Huntington's disease

    Directory of Open Access Journals (Sweden)

    Damian M Cummings

    2010-06-01

    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.

  14. 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.

  15. 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.

  16. Construction of a digital and physical mouse model aimed at the study of electrical shock

    Science.gov (United States)

    Nguyen, Thu T. A.; Shupp, Jeffrey W.; Moffatt, Lauren T.; Ramella-Roman, Jessica C.

    2014-03-01

    Optical methods have been used to investigate electrical injury on animal models such as live mice, rats, and rabbits. Here we introduce a completely digital phantom of a mouse, with the aim of investigating electrical injury through spectroscopic imaging techniques. The basis of our phantom is a three-dimensional digital mouse reconstructed from co-registered computed tomographic images and cryosection by a different group. Image processing algorithms were applied to make the model suitable to Finite Element Analysis of thermal and electrical transport. Our digital model is capable of simulating temperature, voltage, current changes along the animal body during and after electrical shocks.

  17. Evaluation of Mammary Gland Development and Function in Mouse Models

    OpenAIRE

    Plante, Isabelle; Stewart, Michael K.G.; Laird, Dale W.

    2011-01-01

    The human mammary gland is composed of 15-20 lobes that secrete milk into a branching duct system opening at the nipple. Those lobes are themselves composed of a number of terminal duct lobular units made of secretory alveoli and converging ducts1. In mice, a similar architecture is observed at pregnancy in which ducts and alveoli are interspersed within the connective tissue stroma. The mouse mammary gland epithelium is a tree like system of ducts composed of two layers of cells, an inner la...

  18. Structural characterization of mouse neutrophil serine proteases and identification of their substrate specificities: relevance to mouse models of human inflammatory diseases.

    Science.gov (United States)

    Kalupov, Timofey; Brillard-Bourdet, Michèle; Dadé, Sébastien; Serrano, Hélène; Wartelle, Julien; Guyot, Nicolas; Juliano, Luiz; Moreau, Thierry; Belaaouaj, Azzaq; Gauthier, Francis

    2009-12-01

    It is widely accepted that neutrophil serine proteases (NSPs) play a critical role in neutrophil-associated lung inflammatory and tissue-destructive diseases. To investigate NSP pathogenic role(s), various mouse experimental models have been developed that mimic acutely or chronically injured human lungs. We and others are using mouse exposure to cigarette smoke as a model for chronic obstructive pulmonary disease with or without exacerbation. However, the relative contribution of NSPs to lung disease processes as well as their underlying mechanisms remains still poorly understood. And the lack of purified mouse NSPs and their specific substrates have hampered advances in these studies. In this work, we compared mouse and human NSPs and generated three-dimensional models of murine NSPs based on three-dimensional structures of their human homologs. Analyses of these models provided compelling evidence that peptide substrate specificities of human and mouse NSPs are different despite their conserved cleft and close structural resemblance. These studies allowed us to synthesize for the first time novel sensitive fluorescence resonance energy transfer substrates for individual mouse NSPs. Our findings and the newly identified substrates should better our understanding about the role of NSPs in the pathogenesis of cigarette-associated chronic obstructive pulmonary disease as well as other neutrophils-associated inflammatory diseases.

  19. An Intraductal Human-in-mouse Transplantation Model Mimics the Subtypes of Ductal Carcinoma In Situ

    OpenAIRE

    Behbod, Fariba; Kittrell, Frances S; LaMarca, Heather; Kerbawy, Sofia; Heestand, Jessica C; Young, Evelin; Mukhopadhyay, Purna; Yeh, Hung-Wen; Allred, D. Craig; Medina, Daniel; Edwards, David; Hu, Min; Polyak, Kornelia; Rosen, Jeffrey M.

    2009-01-01

    Introduction: Human models of noninvasive breast tumors are limited, and the existing in vivo models do not mimic inter- and intratumoral heterogeneity. Ductal carcinoma in situ (DCIS) is the most common type (80%) of noninvasive breast lesions. The aim of this study was to develop an in vivo model whereby the natural progression of human DCIS might be reproduced and studied. To accomplish this goal, the intraductal human-in-mouse (HIM) transplantation model was developed. The resulting model...

  20. Application of Fuzzy Regression Model to the Prediction of Field Mouse Occurrence Rate

    Institute of Scientific and Technical Information of China (English)

    XU Fei

    2009-01-01

    Expressions were given to describe the closeness between the estimated value and observed value for two asymmetric exponential fuzzy numbers. Based on that, the model was given to solve the question of fuzzy multivariable regression with fuzzy input, fuzzy output and crisp coefficients. Finally, with this model, the prediction of field mouse occurrence rate had been done and the satisfied result was obtained.

  1. 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 i

  2. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    Science.gov (United States)

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models-mainly mouse models-have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  3. Low dose of lipopolysaccharide pretreatment can alleviate the inflammatory response in wound infection mouse model

    Institute of Scientific and Technical Information of China (English)

    Dong Wang; Yang Liu; Yan-Rui Zhao; Jun-Lin Zhou

    2016-01-01

    Purpose:To assess the effects of lipopolysaccharide (LPS) pretreatment on wound infection mouse model and evaluate the biological safety of the optimal pretreatment dose in vivo.Methods:Mice were pretreated with LPS of different doses at 48 and 24 h before femoral medial longitudinal incision was made and infected with different bacteria.Results:It is showed that 0.5 mg/kg/time of LPS pretreatment can significantly alleviate the inflammation in mouse model infected with methicillin-resistances Staphylococcus aureus,methicillin-sensitive S.aureus,Pseudomonas aeruginosa,or Escherichia coli compared with doses of 0.25 mg/kg/time,1 mg/kg/time,and 1.5 mg/kg/time.Conclusions:LP5 pretreatment can alleviate the inflammation in mouse model and the optimal dose is 0.5 mg/kg/time,and meanwhile it does not damage organs' function.

  4. Patient-derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment.

    Science.gov (United States)

    Kuracha, Murali R; Thomas, Peter; Loggie, Brian W; Govindarajan, Venkatesh

    2016-04-01

    Pseudomyxoma peritonei (PMP) is a neoplastic syndrome characterized by peritoneal tumor implants with copious mucinous ascites. The standard of care for PMP patients is aggressive cytoreductive surgery performed in conjunction with heated intraperitoneal chemotherapy. Not all patients are candidates for these procedures and a majority of the patients will have recurrent disease. In addition to secreted mucin, inflammation and fibrosis are central to PMP pathogenesis but the molecular processes that regulate tumor-stromal interactions within the peritoneal tumor microenvironment remain largely unknown. This knowledge is critical not only to elucidate PMP pathobiology but also to identify novel targets for therapy. Here, we report the generation of patient-derived xenograft (PDX) mouse models for PMP and assess the ability of these models to replicate the inflammatory peritoneal microenvironment of human PMP patients. PDX mouse models of low- and high-grade PMP were generated and were of a similar histopathology as human PMP. Cytokines previously shown to be elevated in human PMP were also elevated in PDX ascites. Significant differences in IL-6 and IL-8/KC/MIP2 were seen between human and PDX ascites. Interestingly, these cytokines were mostly secreted by mouse-derived, tumor-associated stromal cells rather than by human-derived PMP tumor cells. Our data suggest that the PMP PDX mouse models are especially suited to the study of tumor-stromal interactions that regulate the peritoneal inflammatory environment in PMP as the tumor and stromal cells in these mouse models are of human and murine origins, respectively. These mouse models are therefore, likely to be useful in vivo surrogates for testing and developing novel therapeutic treatment interventions for PMP.

  5. 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.

  6. 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

  7. 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

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

    Directory of Open Access Journals (Sweden)

    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

  9. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

    Science.gov (United States)

    Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn

    2016-01-01

    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. PMID:27441847

  10. A Novel Three-Dimensional Mouse Embryonic Implantation Model In Vitro

    Institute of Scientific and Technical Information of China (English)

    SONG Yu-xuan; CAO Bin-yun

    2007-01-01

    To regenerate three-dimensional endometrium in vitro as a novel model for studying the mechanism of implantation of embryos, the luminal epithelial cells and stromal cells of the rabbit uterus were separated and cultured in vitro. The type Ⅰ mouse tail collagen was used as scaffolding material. The stromal cells were inoculated in the type Ⅰ mouse tail collagen, and the luminal epithelial cells were inoculated on the type Ⅰ mouse tail collagen to regenerate the endometrium in vitro. The regenerated endometrium was cultured in DMEM-F/12 media containing 100 nmol L-1 progesterone, 10 nM β-estradiol, and 10% fetal bovine serum (FBS) for 3 d. The media were then replaced with CZB containing 100 nM progesterone, 10 nmol L-1 β-estradiol, and 10% FBS, and the mouse blastulas were co-cultured with it. The results of scanning electronic micrography showed that the epithelial cells on the surface of the reconstructed endometrium were covered with numerous slender microvilli and some epithelial cells protruded pinopodes. After culturing for 12 h with the mouse blastula, the shedding, attachment, and implantation of the blastula were observed. The blastula can escape from zona pellucida and attach to the three-dimensional endometrium and is then implanted into it. Thisstudy showed that the reconstructed three-dimensional endometrium can serve as a robust embryo implantation model in vitro.

  11. Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis.

    Science.gov (United States)

    Wu, Xiaoli; Sandhu, Sumit; Nabi, Zinnatun; Ding, Hao

    2012-10-01

    Regulator of telomere length 1 (RTEL1) is a DNA helicase protein that has been demonstrated to be required for the maintenance of telomere length and genomic stability. It has also been found to be essential for DNA homologous recombination during DNA repairing. Human RTEL1 genomic locus (20q13.3) is frequently amplified in multiple types of human cancers, including hepatocellular carcinoma and gastrointestinal tract tumors, indicating that upregulated RTEL1 activity could be important for tumorigenesis. In this study, we have developed a conditional transgenic mouse model that overexpress mouse Rtel1 in a Cre-excision manner. By crossing with a ubiquitous Cre mouse line, we further demonstrated that these established Rtel1 conditional transgenic mice allow to efficiently and highly express a functional Rtel1 that is able to rescue the embryonic defects of Rtel1 null mouse allele. Furthermore, we demonstrated that more than 70% transgenic mice that widely overexpress Rtel1 developed liver tumors that recapitulate many malignant features of human hepatocellular carcinoma (HCC). Our work not only generated a valuable mouse model for determining the role of RTEL1 in the development of cancers, but also provided the first genetic evidence to support that amplification of RTEL1, as observed in several types of human cancers, is tumorigenic. PMID:22238064

  12. Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.

    Science.gov (United States)

    Morini, Elisabetta; Dietrich, Paula; Salani, Monica; Downs, Heather M; Wojtkiewicz, Gregory R; Alli, Shanta; Brenner, Anthony; Nilbratt, Mats; LeClair, John W; Oaklander, Anne Louise; Slaugenhaupt, Susan A; Dragatsis, Ioannis

    2016-03-15

    Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect. PMID:26769677

  13. 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

    2013-01-01

    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. PMID:23863947

  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. 小鼠模型与人类疾病%The Mouse Model and Human Disease

    Institute of Scientific and Technical Information of China (English)

    孔祥复; 黄建东

    2001-01-01

    The mouse is an ideal model organism for studies of human disease, because mouse is physiologically very similar to human. Also, there is a large genetic reservoir of potential models of human diseases that has been generated. In addition, high-resolution genetic and physical linkage maps are now available and the sequence of mouse genome will be completed in the near future. Furthermore, the techniques necessary for the modification of mouse genome, such as transgenic and knockout techniques, and chromosome engineering methods have been established. These techniques enable us to introduce any mutations anywhere in the mouse genome. The methods for analyzing complex genetic diseases also have been developed. These advances facilitate the identification and cloning of mouse disease loci and the establishment of new models. It makes mouse the model organism of choice by academic and industrial researchers to study human diseases. In Part I of this review, we summarize the classical and modern approaches that provide the basis of establishing mouse model of human diseases. In the following parts, we will list more than 100 mouse models of human diseases. In most of these models, the mouse mutant phenotype closely resembles the human disease phenotype. These mouse models are valuable sources for the understanding of the human diseases and they can be used to develop strategies for prevention and treatment of the diseases.%小鼠是人类疾病理想的动物模型,不仅因为小鼠在生理上与人类极为相似而且小鼠的遗传资源非常丰富,其大量的遗传变异可作为研究人类疾病的借鉴。另外,高分辨率的小鼠遗传及物理连锁图谱已经建成,小鼠基因组的测序工作不久即将完成,而且修饰小鼠基因组的技术(包括建立转基因小鼠、基因敲除、以及改建小鼠染色体的技术)也已具备;分析复杂遗传病的方法也相继建立……。这些进展加速了对小鼠疾病基因

  16. Overview of KRAS-Driven Genetically Engineered Mouse Models of Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Sheridan, Clare; Downward, Julian

    2015-01-01

    KRAS, the most frequently mutated oncogene in non-small cell lung cancer, has been utilized extensively to model human lung adenocarcinomas. The results from such studies have enhanced considerably an understanding of the relationship between KRAS and the development of lung cancer. Detailed in this overview are the features of various KRAS-driven genetically engineered mouse models (GEMMs) of non-small cell lung cancer, their utilization, and the potential of these models for the study of lung cancer biology.

  17. Human androgen deficiency: insights gained from androgen receptor knockout mouse models

    OpenAIRE

    Kesha Rana; Davey, Rachel A; Zajac, Jeffrey D

    2014-01-01

    The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor (AR) through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout (ARKO) models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immu...

  18. A Comparison of Neuroinflammation to Implanted Microelectrodes in Rat and Mouse Models

    OpenAIRE

    Potter-Baker, Kelsey A.; Ravikumar, Madhumitha; Burke, Alan A.; Meador, William D.; Householder, Kyle T.; Buck, Amy C.; Sunil, Smrithi; Stewart, Wade G.; Anna, Jake P.; Tomaszewski, William H.; Capadona, Jeffrey R.

    2014-01-01

    Rat models have emerged as a common tool to study neuroinflammation to intracortical microelectrodes. While a number of studies have attempted to understand the factors resulting in neuroinflammation using rat models, a complete understanding of key mechanistic pathways remains elusive. Transgenic mouse models, however, could facilitate a deeper understanding of mechanistic pathways due to an ease of genetic alteration. Therefore, the goal of the present study is to compare neuroinflammation ...

  19. Altered exploration and sensorimotor gating of the chakragati mouse model of schizophrenia

    OpenAIRE

    Young, Jared W.; RATTY, Anil; Gavin S Dawe; Geyer, Mark A.

    2014-01-01

    Schizophrenia is a prevalent neurodevelopmental psychiatric disorder with poor prognosis and limited understanding of its etiology. This limited etiological understanding renders developing animal models of schizophrenia difficult. While attempts are made to recreate putative etiologies in models, these models may only enable the generation of treatments targeted at the mechanisms manipulated. Although the chakragati mouse was not created as a result of a specific gene targe...

  20. Sexually Dimorphic, Developmental, and Chronobiological Behavioral Profiles of a Mouse Mania Model

    OpenAIRE

    Michael C Saul; Sharon A Stevenson; Gammie, Stephen C.

    2013-01-01

    Bipolar disorders are heritable psychiatric conditions often abstracted by separate animal models for mania and depression. The principal mania models involve transgenic manipulations or treatment with stimulants. An additional approach involves analysis of naturally occurring mania models including an inbred strain our lab has recently characterized, the Madison (MSN) mouse strain. These mice show a suite of behavioral and neural genetic alterations analogous to manic aspects of bipolar diso...

  1. Mouse model of ischemic acute kidney injury: technical notes and tricks

    OpenAIRE

    Wei, Qingqing; Zheng DONG

    2012-01-01

    Renal ischemia-reperfusion leads to acute kidney injury (AKI), a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models, both in vitro and in vivo, have been used to study the pathogenic mechanisms of ischemic AKI and to test renoprotective strategies. Among them, the mouse model of renal clamping is popular, mainly due to the availability of transgenic models and the relatively small animal size for drug testing. However, the ...

  2. Blood biomarkers in a mouse model of CADASIL.

    Science.gov (United States)

    Primo, Vincent; Graham, Mark; Bigger-Allen, Alexander A; Chick, Joel M; Ospina, Carolina; Quiroz, Yakeel T; Manent, Jan; Gygi, Steven P; Lopera, Francisco; D'Amore, Patricia A; Arboleda-Velasquez, Joseph F

    2016-08-01

    Mutations in NOTCH 3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a neurological disorder characterized by stroke, and vascular cognitive impairment and dementia. Loss of vascular smooth muscle cells (VSMC) and accumulation of granular osmiophilic material (GOM) deposits are hallmarks of CADASIL. There are no therapies for CADASIL and experimental endpoints to examine the preclinical efficacy of potential drugs are lacking. This study aims to use a mouse carrying the C455R mutation in Notch 3 to identify biomarkers associated with CADASIL. Mass spectrometry and antibody arrays were used to explore the aorta and blood proteomes of CADASIL mice, ELISA assays were utilized for biomarker validation, a ligand-dependent assay was applied to examine the relationship between Notch signaling and biomarker expression, and retinal histology was performed for quantification of VSMC loss in arteries. Two-hundred day-old mice with the C455R CADASIL mutation in Notch 3 mice display robust VSMC loss in retinal arteries and had increased plasma levels of collagen18α1/endostatin (col18α1) and high-temperature requirement A serine peptidase 1 (HTRA1) and reduced levels of Notch 3 extracellular domain (N3ECD), compared to control wild type mice. Measurements of plasma endostatin, HTRA1 and N3ECD, along with VSMC quantification in retinal arteries, may serve as surrogate endpoints for assessing efficacy in preclinical therapeutic studies of CADASIL using mice. PMID:27174004

  3. 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 occ

  4. The origin of Pasteurella multocida impacts pathology and inflammation when assessed in a mouse model

    DEFF Research Database (Denmark)

    Pors, Susanne E.; Chadfield, Mark S.; Sorensen, Dorte B.;

    2016-01-01

    Host-pathogen interactions of Pasteurella multocida isolates of different origin were studied in a mouse model, focusing on pathology, bacterial load and expression of the metalloproteinase MMP9 and its inhibitor TIMP1. Intranasal inoculation with one of three doses (10(6), 10(4), 10(2) CFU...

  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) cho

  6. 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 C57Bl/6×FV

  7. Mouse models of graft-versus-host disease: advances and limitations

    Directory of Open Access Journals (Sweden)

    Mark A. Schroeder

    2011-05-01

    Full Text Available The limiting factor for successful hematopoietic stem cell transplantation (HSCT is graft-versus-host disease (GvHD, a post-transplant disorder that results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. Mouse models of GvHD have provided important insights into the pathophysiology of this disease, which have helped to improve the success rate of HSCT in humans. The kinetics with which GvHD develops distinguishes acute from chronic GvHD, and it is clear from studies of mouse models of GvHD (and studies of human HSCT that the pathophysiology of these two forms is also distinct. Mouse models also further the basic understanding of the immunological responses involved in GvHD pathology, such as antigen recognition and presentation, the involvement of the thymus and immune reconstitution after transplantation. In this Perspective, we provide an overview of currently available mouse models of acute and chronic GvHD, highlighting their benefits and limitations, and discuss research and clinical opportunities for the future.

  8. Neuroprotective Effects of Voluntary Exercise in an Inherited Retinal Degeneration Mouse Model

    OpenAIRE

    Hanif, Adam M.; Lawson, Eric C.; Prunty, Megan; Gogniat, Marissa; Aung, Moe H.; Chakraborty, Ranjay; Boatright, Jeffrey H.; Pardue, Machelle T.

    2015-01-01

    Voluntary running wheel exercise significantly decreases the rate of photoreceptor degeneration and visual acuity loss associated with the rd10 mouse model. Furthermore, systemic administration of a TrkB antagonist, ANA-12, blocks the protective effects on structure and function.

  9. New Mouse Model May Aid in Developing Effective Therapies for Ovarian Cancer | Poster

    Science.gov (United States)

    By Frank Blanchard, Staff Writer A new genetically engineered mouse model appears promising as an effective tool for preclinical testing of novel therapies for ovarian cancer, which tends to be diagnosed in late stage. There are few effective treatments for the disease.

  10. 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

  11. Local and systemic effects of angiotensin receptor blockade in an emphysema mouse model

    OpenAIRE

    Raupach, Tobias; Lüthje, Lars; Kögler, Harald; de Duve, Christian; Schweda, Frank; Hasenfuß, Gerd; Andreas, Stefan

    2011-01-01

    Abstract Objectives COPD with emphysema causes marked neurohumoral activation. Angiotensin II receptors are highly expressed within the lung and interfere with mechanisms involved in the progression of emphysema. This study examined the effects of an angiotensin II receptor blocker (ARB) on pulmonary and systemic manifestations of emphysema in a mouse model. Methods Female NMRI mice received five intratracheal instillations of porcine pancreatic ela...

  12. 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...

  13. Comparative Exposure to Soy Biodiesel Emissions in an Allergic Mouse Model

    Science.gov (United States)

    We assessed the immunological effects following inhalation of emissions from 100% Soy biodiesel (S100) or a 20% mix with conventional petrodiesel (S20), in a house dust mite (HDM) allergic Balb/cJ mouse model. Female mice (8/group) were exposed whole body (4 hr/d, 5 d/wk, 4wk) to...

  14. 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…

  15. Defective Surfactant Secretion in a Mouse Model of Hermansky-Pudlak Syndrome

    OpenAIRE

    Guttentag, Susan H.; Akhtar, Amana; Tao, Jian-Qin; Atochina, Elena; Rusiniak, Michael E.; Swank, Richard T.; Bates, Sandra R.

    2005-01-01

    Hermansky-Pudlak syndrome (HPS) in humans represents a family of disorders of lysosome-related organelle biogenesis associated with severe, progressive pulmonary disease. Human case reports and a mouse model of HPS, the pale ear/pearl mouse (ep/pe), exhibit giant lamellar bodies (GLB) in type II alveolar epithelial cells. We examined surfactant proteins and phospholipid from ep/pe mice to elucidate the process of GLB formation. The 2.8-fold enrichment of tissue phospholipids in ep/pe mice res...

  16. Genotype, Phenotype, and Karyotype Correlation in the XO Mouse Model of Turner Syndrome

    OpenAIRE

    Probst, Frank J.; Cooper, Mitchell Lance; Cheung, Sau Wai; Justice, Monica J.

    2008-01-01

    The murine model for Turner Syndrome is the XO mouse. Unlike their human counterparts, XO mice are typically fertile, and their lack of a second sex chromosome can be transmitted from one generation to the next as an X-linked dominant trait with male lethality. The introduction of an X-linked coat-color marker (tabby) has greatly facilitated the maintenance of this useful mouse strain. XO mice can be produced in large numbers, generation after generation, and rapidly identified on the basis o...

  17. In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models

    OpenAIRE

    Brož, Daniela Kenzelmann; Attardi, Laura D.

    2010-01-01

    p53 is a crucial tumor suppressor, as evidenced by the high propensity for p53 mutation during human cancer development. Already more than a decade ago, p53 knockout mice confirmed that p53 is critical for preventing tumorigenesis. More recently, a host of p53 knock-in mouse strains has been generated, with the aim of either more precisely modeling p53 mutations in human cancer or better understanding p53's regulation and downstream activities. In the first category, several mouse strains exp...

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Michael A. Mcilhatton

    2016-01-01

    Full Text Available 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.

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

    Science.gov (United States)

    Mcilhatton, Michael A; Boivin, Gregory P; Groden, Joanna

    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

  1. Small-diameter biodegradable scaffolds for functional vascular tissue engineering in the mouse model.

    Science.gov (United States)

    Roh, Jason D; Nelson, Gregory N; Brennan, Matthew P; Mirensky, Tamar L; Yi, Tai; Hazlett, Tyrone F; Tellides, George; Sinusas, Albert J; Pober, Jordan S; Saltzman, W M; Kyriakides, Themis R; Breuer, Christopher K

    2008-04-01

    The development of neotissue in tissue engineered vascular grafts remains poorly understood. Advances in mouse genetic models have been highly informative in the study of vascular biology, but have been inaccessible to vascular tissue engineers due to technical limitations on the use of mouse recipients. To this end, we have developed a method for constructing sub-1mm internal diameter (ID) biodegradable scaffolds utilizing a dual cylinder chamber molding system and a hybrid polyester sealant scaled for use in a mouse model. Scaffolds constructed from either polyglycolic acid or poly-l-lactic acid nonwoven felts demonstrated sufficient porosity, biomechanical profile, and biocompatibility to function as vascular grafts. The scaffolds implanted as either inferior vena cava or aortic interposition grafts in SCID/bg mice demonstrated excellent patency without evidence of thromboembolic complications or aneurysm formation. A foreign body immune response was observed with marked macrophage infiltration and giant cell formation by post-operative week 3. Organized vascular neotissue, consisting of endothelialization, medial generation, and collagen deposition, was evident within the internal lumen of the scaffolds by post-operative week 6. These results present the ability to create sub-1mm ID biodegradable tubular scaffolds that are functional as vascular grafts, and provide an experimental approach for the study of vascular tissue engineering using mouse models. PMID:18164056

  2. Development and function of human innate immune cells in a humanized mouse model

    Science.gov (United States)

    Rongvaux, Anthony; Willinger, Tim; Martinek, Jan; Strowig, Till; Gearty, Sofia V.; Teichmann, Lino L.; Saito, Yasuyuki; Marches, Florentina; Halene, Stephanie; Palucka, A. Karolina; Manz, Markus G.; Flavell, Richard A.

    2014-01-01

    Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models are unable to support development of human innate immune cells, including myeloid cells and NK cells. Here we describe a mouse strain, called MI(S)TRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked in to their respective mouse loci. The human cytokines support the development and function of monocytes/macrophages and natural killer cells derived from human fetal liver or adult CD34+ progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MI(S)TRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology. PMID:24633240

  3. The SCID-hu mouse as a model for HIV-1 infection.

    Science.gov (United States)

    Aldrovandi, G M; Feuer, G; Gao, L; Jamieson, B; Kristeva, M; Chen, I S; Zack, J A

    1993-06-24

    During normal fetal ontogeny, one of the first organs to harbour CD4-positive cells is the thymus. This organ could therefore be one of the earliest targets infected by human immunodeficiency virus type 1 (HIV-1) in utero. HIV-1-infected cells and pathological abnormalities of the thymus have been seen in HIV-1-infected adults and children, and in some fetuses aborted from infected women. Studies of HIV-1 pathogenesis have been hampered by lack of a suitable animal model system. Here we use the SCID-hu mouse as a model to investigate the effect of virus infection on human tissue. The mouse is homozygous for the severe combined immunodeficiency (SCID) defect. The model is constructed by implanting human fetal liver and thymus under the mouse kidney capsule. A conjoint human organ develops, which allows normal maturation of human thymocytes. After direct inoculation of HIV-1 into these implants, we observed severe depletion of human CD4-bearing cells within a few weeks of infection. This correlated with increasing virus load in the implants. Thus the SCID-hu mouse may be a useful in vivo system for the study of HIV-1-induced pathology.

  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. Application of Novel Rotation Angular Model for 3D Mouse System Based on MEMS Accelerometers

    Institute of Scientific and Technical Information of China (English)

    QIAN Li; CHEN Wen-yuan; XU Guo-ping

    2009-01-01

    A new scheme is proposed to model 3D angular motion of a revolving regular object with miniature, low-cost micro electro mechanical systems (MEMS) accelerometers (instead of gyroscope), which is employed in 3D mouse system. To sense 3D angular motion, the static property of MEMS accelerometer, sensitive to gravity acceleration, is exploited. With the three outputs of configured accelerometers, the proposed model is implemented to get the rotary motion of the rigid object. In order to validate the effectiveness of the proposed model, an input device is developed with the configuration of the scheme. Experimental results show that a simulated 3D cube can accurately track the rotation of the input device. The result indicates the feasibility and effectiveness of the proposed model in the 3D mouse system.

  6. Photodynamic therapy for breast cancer in a BALB/c mouse model

    OpenAIRE

    Ahn, Tae-Gyu; Lee, Byoung-Rai; Choi, Eun-Young; Kim, Dong Won; Han, Sei-Jun

    2012-01-01

    Objective Photodynamic therapy (PDT) has been used for superficial neoplasms and its usage has been recently extended to deeper lesions. The purpose of this study was to observe whether or not PDT can cure breast cancer in the solid tumor model, and to define the critical point of laser amount for killing the cancer cells. Methods Twenty four BALB/c mouse models with subcutaneous EMT6 mammary carcinomas were prepared. Mice were divided into eight groups depending on the amount of illumination...

  7. Optimized Mouse Model for the Imaging of Tumor Metastasis upon Experimental Therapy

    OpenAIRE

    Sergio Lavilla-Alonso; Usama Abo-Ramadan; Juha Halavaara; Sophie Escutenaire; Turgut Tatlisumak; Kalle Saksela; Anna Kanerva; Akseli Hemminki; Sari Pesonen

    2011-01-01

    Development of new cancer treatments focuses increasingly on the relation of cancer tissue with its microenvironment. A major obstacle for the development of new anti-cancer therapies has been the lack of relevant animal models that would reproduce all the events involved in disease progression from the early-stage primary tumor until the development of mature metastatic tissue. To this end, we have developed a readily imageable mouse model of colorectal cancer featuring highly reproducible f...

  8. Bezafibrate improves mitochondrial function in the CNS of a mouse model of mitochondrial encephalopathy

    OpenAIRE

    Noe, Natalie; Dillon, Lloye; Lellek, Veronika; Diaz, Francisca; Hida, Aline; Carlos T. Moraes; Wenz, Tina

    2012-01-01

    Mitochondrial dysfunction frequently affects the central nervous system. Here, we investigated the effect of bezafibrate treatment on neuronal mitochondrial function and its impact on the progression of a mitochondrial encephalopathy. We used a murine model with a forebrain-specific cytochrome c oxidase deficiency caused by conditional deletion of the COX10 gene. In this mouse model, bezafibrate-administration improved the phenotype of the mice associated with an increase in mitochondrial pro...

  9. Establishment of mouse lung tumor models and development of new therapeutic approaches

    OpenAIRE

    Savai, Rajkumar

    2005-01-01

    Two mouse models of lung cancer were used to investigate cancer progression, cancer treatment, and cancer imaging. One model was established by subcutaneous injection of human adenocarcinoma A549 cells and lewis lung carcinoma (LLC1) cells, the other by intratracheal instillation of LLC1 cells. In the first study, the role of HIF-1 in tumor progression was investigated. Overexpression of HIF-1alpha by genetic alteration of adenocarcinoma cells decreased tumor size, due to decreased pr...

  10. Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration

    OpenAIRE

    Hesketh, Emily E.; Czopek, Alicja; Clay, Michael; Borthwick, Gary; Ferenbach, David; Kluth, David; Hughes, Jeremy

    2014-01-01

    Renal ischaemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) in patients and occlusion of renal blood flow is unavoidable during renal transplantation. Experimental models that accurately and reproducibly recapitulate renal IRI are crucial in dissecting the pathophysiology of AKI and the development of novel therapeutic agents. Presented here is a mouse model of renal IRI that results in reproducible AKI. This is achieved by a midline laparotomy approach for the sur...

  11. Genetically engineered mouse models for skin research: taking the next step

    OpenAIRE

    Chen, Jiang; Roop, Dennis R.

    2008-01-01

    Genetically engineered mouse models are invaluable to investigators in nearly all areas of biomedical research. The use of genetically engineered mice has allowed researchers to explore fundamental functions of genes in a mammal that shares substantial similarities with human physiology and pathology. Genetically engineered mice are often used as animal models of human diseases that are vital tools in investigating disease development and in developing and testing novel therapies. Gene target...

  12. Infertility in Females with Cystic Fibrosis Is Multifactorial: Evidence from Mouse Models

    OpenAIRE

    Hodges, Craig A.; Palmert, Mark R.; Drumm, Mitchell L.

    2008-01-01

    Infertility is commonly associated with cystic fibrosis (CF). Although infertility in men with CF has been thoroughly investigated, the infertility observed in women with CF has not been well studied. To investigate female infertility associated with CF, we used two independently derived mouse models of CF. Both of these models displayed decreased fertility characterized by a reduction in litter number and litter size. Our findings suggest that much of the reduced fertility in these mice orig...

  13. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression

    OpenAIRE

    Flavie eDarcet; Indira eMendez-David; Laurent eTritschler; Gardier, Alain M.; Jean-Philippe eGuilloux; Denis Joseph David

    2014-01-01

    Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders. Such deficits have been observed in various animal models based on environmental stress.Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel object r...

  14. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression

    OpenAIRE

    Darcet, Flavie; Mendez-David, Indira; Tritschler, Laurent; Gardier, Alain M.; Guilloux, Jean-Philippe; David, Denis J.

    2014-01-01

    Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders (MDDs). Such deficits have been observed in various animal models based on environmental stress. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel ...

  15. Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

    OpenAIRE

    Bertrand Perroud; Paymaan Jafar-Nejad; Wikoff, William R.; Gatchel, Jennifer R.; Lu Wang; Barupal, Dinesh K.; Juan Crespo-Barreto; Oliver Fiehn; Zoghbi, Huda Y.; Rima Kaddurah-Daouk

    2013-01-01

    We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1(154Q/+)). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+) mice, with and without lithium treatment, were performed using gas chromatogra...

  16. Ghrelin and eating behavior: evidence and insights from genetically-modified mouse models

    OpenAIRE

    Aki eUchida; Zigman, Jeffrey M.; Mario ePerello

    2013-01-01

    Ghrelin is an octanoylated peptide hormone, produced by endocrine cells of the stomach, which acts in the brain to increase food intake and body weight. Our understanding of the mechanisms underlying ghrelin’s effects on eating behaviors has been greatly improved by the generation and study of several genetically manipulated mouse models.These models include mice overexpressing ghrelin and also mice with genetic deletion of ghrelin, the ghrelin receptor [the growth hormone secretagogue recep...

  17. DISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Tyler eCash-Padgett

    2013-09-01

    Full Text Available DISC1 was discovered in a Scottish pedigree in which a chromosomal translocation that breaks this gene segregates with psychiatric disorders, mainly depression and schizophrenia. Linkage and association studies in diverse populations support DISC1 as a susceptibility gene to a variety of neuropsychiatric disorders. Many Disc1 mouse models have been generated to study its neuronal functions. These mouse models display variable phenotypes, some of them relevant to schizophrenia, others to depression.The Disc1 mouse models are popular genetic models for studying gene-environment interactions in schizophrenia. Five different Disc1 models have been combined with environmental factors. The environmental stressors employed can be classified as either early immune activation or later social paradigms. These studies cover major time points along the neurodevelopmental trajectory: prenatal, early postnatal, adolescence, and adulthood. Various combinations of molecular, anatomical and behavioral methods have been used to assess the outcomes. Additionally, three of the studies sought to rescue the resulting abnormalities.Here we provide background on the environmental paradigms used, summarize the results of these studies combining Disc1 mouse models with environmental stressors and discuss what we can learn and how to proceed. A major question is how the genetic and environmental factors determine which psychiatric disorder will be clinically manifested. To address this we can take advantage of the many Disc1 models available and expose them to the same environmental stressor. The complementary experiment would be to expose the same model to different environmental stressors. DISC1 is an ideal gene for this approach, since in the Scottish pedigree the same chromosomal translocation results in different psychiatric conditions.

  18. Estimating Lead (Pb) Bioavailability In A Mouse Model

    Science.gov (United States)

    Children are exposed to Pb through ingestion of Pb-contaminated soil. Soil Pb bioavailability is estimated using animal models or with chemically defined in vitro assays that measure bioaccessibility. However, bioavailability estimates in a large animal model (e.g., swine) can be...

  19. COMPARATIVE EFFICIENCIES STUDY OF SLOT MODEL AND MOUSE MODEL IN PRESSURISED PIPE FLOW

    Directory of Open Access Journals (Sweden)

    Saroj K. Pandit

    2014-01-01

    Full Text Available The flow in sewers is unsteady and variable between free-surfac e to full pipe pressurized flow. Sewers are designed on the basis of free surf ace flow (gravity flow however they may carry pressurized flow. Preissmann Slot concep t is widely used numerical approach in unsteady free surface-pressurized flow as it provides the advantage of using free surface flow as a single type flow. Slo t concept uses the Saint- Venant’s equations as a basic equation for one-dimensional unst eady free surface flow. This paper includes two different numerical models using Saint Venant’s equations. The Saint Venant’s e quations of continuity and momen tum are solved by the Method of Characteristics and presented in forms for direct substitution into FORTRAN programming for numerical analysis in the first model. The MOUSE model carries out computation of unsteady flows which is founde d on an implicit, finite difference numerical solut ion of the basic one dimension al Saint Venant’s equations of free surface flow. The simulation results are comp ared to analyze the nature and degree of errors for further improvement.

  20. Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa.

    Science.gov (United States)

    Roche, Sarah L; Wyse-Jackson, Alice C; Byrne, Ashleigh M; Ruiz-Lopez, Ana M; Cotter, Thomas G

    2016-01-01

    Mouse models of retinitis pigmentosa (RP) are essential tools in the pursuit to understand fully what cell types and processes underlie the degeneration observed in RP. Knowledge of these processes is required if we are to develop successful therapies to treat this currently incurable disease. We have used the rd10 mouse model of RP to study retinal morphology prior to photoreceptor loss, using immunohistochemistry and confocal microscopy on cryosections, since little is known about how the mutation affects the retina during this period. We report novel findings that the mutation in the rd10 mouse results in retinal abnormalities earlier than was previously thought. Defects in rod and cone outer segments, bipolar cells, amacrine cells and photoreceptor synapses were apparent in the retina during early stages of postnatal retinal development and prior to the loss of photoreceptors. Additionally, we observed a dramatic response of glial cells during this period. Microglia responded as early as postnatal day (P) 5; ?13 days before any photoreceptor loss is detected with Müller glia and astrocytes exhibiting changes from P10 and P15 respectively. Overall, these findings present pathological aspects to the postnatal development of the rd10 retina, contributing significantly to our understanding of disease onset and progression in the rd10 mouse and provide a valuable resource for the study of retinal dystrophies. PMID:27160072

  1. A Mathematical Model of Skeletal Muscle Disease and Immune Response in the mdx Mouse

    Directory of Open Access Journals (Sweden)

    Abdul Salam Jarrah

    2014-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.

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

    OpenAIRE

    Dorner, Marcus; Horwitz, Joshua A.; Robbins, Justin B.; Barry, Walter T.; Feng, Qian; Mu, Kathy; Jones, Christopher T.; Schoggins, John W.; Catanese, Maria Teresa; Burton, Dennis R.; Law, Mansun; Rice, Charles M.; Ploss, Alexander

    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. While xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin (OCLN) comprise the minimal human factors required to re...

  3. 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...

  4. A model for gas and nutrient exchange in the chorionic vasculature system of the mouse placenta

    Science.gov (United States)

    Mirbod, Parisa; Sled, John

    2015-11-01

    The aim of this study is to develop an analytical model for the oxygen and nutrient transport from the umbilical cord to the small villous capillaries. The nutrient and carbon dioxide removal from the fetal cotyledons in the mouse placental system has also been considered. This model describes the mass transfer between the fetal and the maternal red blood cells in the chorionic arterial vasculature system. The model reveals the detail fetal vasculature system and its geometry and the precise mechanisms of mass transfer through the placenta. The dimensions of the villous capillaries, the total length of the villous trees, the total villi surface area, and the total resistance to mass transport in the fetal villous trees has also been defined. This is the first effort to explain the reason why there are at least 7 lobules in the mouse placenta from the fluid dynamics point of view.

  5. Mouse models in liver cancer research: A review of current literature

    Institute of Scientific and Technical Information of China (English)

    Martijn WH Leenders; Maarten W Nijkamp; Inne HM Borel Rinkes

    2008-01-01

    Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in EasL-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used,especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma (HCC), as this is by far the most common Lype of primary liver cancer, accounting for 70%-85% of cases.

  6. Fulminant liver failure models with subsequent encephalopathy in the mouse

    Institute of Scientific and Technical Information of China (English)

    Ann-Marie T Baine; Tomohide Hori; Feng Chen; Lindsay B Gardner; Shinji Uemoto; Justin H Nguyen

    2011-01-01

    BACKGROUND:  A reliable model of fulminant liver failure (FLF) is urgently required in this research field. This study aimed to develop a murine FLF model. METHODS: We used three groups of male C57BL/6 mice:control, with azoxymethane treatment (AOM group), and with galactosamine and tumor necrosis factor-alpha treatment (Gal+TNF-α group). The effects of body temperature (BT) control on survival in all three groups were investigated. Using BT control, we compared the survival, histopathological findings and biochemical/coagulation profiles between the two experimental groups. The effects of hydration on international normalized ratios of prothrombin time (PT-INRs) were also checked. Dose-dependent survival curves were constructed for both experimental groups. Neurological behavior was assessed using a coma scale. RESULTS: No unexpected BT effects were seen in the control group. The AOM group, but not the Gal+TNF-α group, showed a significant difference in survival curves between those with and without BT care. Histopathological assessment showed consistent FLF findings in both experimental groups with BT care. There were significant differences between the experimental groups in aspartate aminotransferase levels and PT-INRs, and significant differences in PT-INRs between the sufficiently and insufficiently hydrated groups. There were significant differences between FLF models in the duration of each coma stage, with significant differences in stages 1 and 3 as percentages of the disease state (stages 1-4). The two FLF models with BT care showed different survival curves in the dose-dependent survival study. CONCLUSIONS: AOM provides a good FLF model, but requires a specialized environment and careful BT control. Other FLF models may also be useful, depending on the research purpose. Thoughtful attention to caregiving and close observation are indispensable for successful FLF models.

  7. 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.

  8. Development of a transgenic mouse model to study the immunogenicity of recombinant human insulin.

    Science.gov (United States)

    Torosantucci, Riccardo; Brinks, Vera; Kijanka, Grzegorz; Halim, Liem Andhyk; Sauerborn, Melody; Schellekens, Huub; Jiskoot, Wim

    2014-05-01

    Mouse models are commonly used to assess the immunogenicity of therapeutic proteins and to investigate the immunological processes leading to antidrug antibodies. The aim of this work was to develop a transgenic (TG) Balb/c mouse model for evaluating the immunogenicity of recombinant human insulin (insulin) formulations. Validation of the model was performed by measuring the antibody response against plain and particulate insulin in TG and nontransgenic (NTG) mice. Intraperitoneal administration of insulin (20 μg/dose, 12 doses over a period of 4 weeks) did not break the immune tolerance of the TG mice, whereas it did elicit antibodies in NTG mice. The immune tolerance of TG mice could be circumvented, albeit at low titers, by administering insulin covalently bound to 50-nm polystyrene nanoparticles. The TG mouse model was employed to compare the immunogenicity of oxidized aggregated insulin, oxidized nonaggregated insulin, and three commercially available formulations of insulin variants (i.e., Levemir®, Insulatard®, and Actrapid®). Oxidized insulin, aggregated or nonaggregated, was moderately immunogenic in TG mice (50% and 33% responders, respectively), whereas the immunogenicity of the commercial formulations was low. This model can be used to compare the immunogenicity of insulin formulations and to study immune mechanisms of antibody formation against insulin. PMID:24619587

  9. Mouse models of advanced spontaneous metastasis for experimental therapeutics.

    Science.gov (United States)

    Francia, Giulio; Cruz-Munoz, William; Man, Shan; Xu, Ping; Kerbel, Robert S

    2011-02-01

    An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models.

  10. 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...... testing of compounds that could inhibit metastasis. As a result, proper quantification of metastases from in vivo models is of the utmost significance. Here, we provide a detailed protocol for collecting and handling lung tissues from mice, and guidance for subsequent analysis of metastases, as well...

  11. 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.

  12. Mouse Models Applied to the Research of Pharmacological Treatments in Asthma.

    Science.gov (United States)

    Marqués-García, Fernando; Marcos-Vadillo, Elena

    2016-01-01

    Models developed for the study of asthma mechanisms can be used to investigate new compounds with pharmacological activity against this disease. The increasing number of compounds requires a preclinical evaluation before starting the application in humans. Preclinical evaluation in animal models reduces the number of clinical trials positively impacting in the cost and in safety. In this chapter, three protocols for the study of drugs are shown: a model to investigate corticoids as a classical treatment of asthma; a protocol to test the effects of retinoic acid (RA) on asthma; and a mouse model to test new therapies in asthma as monoclonal antibodies. PMID:27300543

  13. Establishment of a uremic apolipoprotein E knockout mouse model to explore the mechanism of uremic atherosclerosis

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Objective To establish a uremic apoE-/-mouse model to observe serum biochemical parameters and features of aortic root atherosclerosis (AS) in the model. Methods A uremic model was induced surgically in apoE-/- mice:electrocautery of the right kidney at 8 weeks of age and nephrectomy (NX) of the left one 2 weeks later. Control mice were sham-operated. Two weeks after NX,renal functions were detected in the uremic and control mice to evaluate the efficiency of the model. After 10 weeks of NX,blood samples we...

  14. 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...

  15. 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.

  16. Novel basophil- or eosinophil-depleted mouse models for functional analyses of allergic inflammation.

    Directory of Open Access Journals (Sweden)

    Kunie Matsuoka

    Full Text Available Basophils and eosinophils play important roles in various host defense mechanisms but also act as harmful effectors in allergic disorders. We generated novel basophil- and eosinophil-depletion mouse models by introducing the human diphtheria toxin (DT receptor gene under the control of the mouse CD203c and the eosinophil peroxidase promoter, respectively, to study the critical roles of these cells in the immunological response. These mice exhibited selective depletion of the target cells upon DT administration. In the basophil-depletion model, DT administration attenuated a drop in body temperature in IgG-mediated systemic anaphylaxis in a dose-dependent manner and almost completely abolished the development of ear swelling in IgE-mediated chronic allergic inflammation (IgE-CAI, a typical skin swelling reaction with massive eosinophil infiltration. In contrast, in the eosinophil-depletion model, DT administration ameliorated the ear swelling in IgE-CAI whether DT was administered before, simultaneously, or after, antigen challenge, with significantly lower numbers of eosinophils infiltrating into the swelling site. These results confirm that basophils and eosinophils act as the initiator and the effector, respectively, in IgE-CAI. In addition, antibody array analysis suggested that eotaxin-2 is a principal chemokine that attracts proinflammatory cells, leading to chronic allergic inflammation. Thus, the two mouse models established in this study are potentially useful and powerful tools for studying the in vivo roles of basophils and eosinophils. The combination of basophil- and eosinophil-depletion mouse models provides a new approach to understanding the complicated mechanism of allergic inflammation in conditions such as atopic dermatitis and asthma.

  17. 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

  18. A mouse model of mitochondrial complex III dysfunction induced by myxothiazol

    Energy Technology Data Exchange (ETDEWEB)

    Davoudi, Mina [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Kallijärvi, Jukka; Marjavaara, Sanna [Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Kotarsky, Heike; Hansson, Eva [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Levéen, Per [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Fellman, Vineta, E-mail: Vineta.Fellman@med.lu.se [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki 00029 (Finland)

    2014-04-18

    Highlights: • Reversible chemical inhibition of complex III in wild type mouse. • Myxothiazol causes decreased complex III activity in mouse liver. • The model is useful for therapeutic trials to improve mitochondrial function. - Abstract: Myxothiazol is a respiratory chain complex III (CIII) inhibitor that binds to the ubiquinol oxidation site Qo of CIII. It blocks electron transfer from ubiquinol to cytochrome b and thus inhibits CIII activity. It has been utilized as a tool in studies of respiratory chain function in in vitro and cell culture models. We developed a mouse model of biochemically induced and reversible CIII inhibition using myxothiazol. We administered myxothiazol intraperitoneally at a dose of 0.56 mg/kg to C57Bl/J6 mice every 24 h and assessed CIII activity, histology, lipid content, supercomplex formation, and gene expression in the livers of the mice. A reversible CIII activity decrease to 50% of control value occurred at 2 h post-injection. At 74 h only minor histological changes in the liver were found, supercomplex formation was preserved and no significant changes in the expression of genes indicating hepatotoxicity or inflammation were found. Thus, myxothiazol-induced CIII inhibition can be induced in mice for four days in a row without overt hepatotoxicity or lethality. This model could be utilized in further studies of respiratory chain function and pharmacological approaches to mitochondrial hepatopathies.

  19. MicroRNAs and Alzheimer's Disease Mouse Models: Current Insights and Future Research Avenues

    Directory of Open Access Journals (Sweden)

    Charlotte Delay

    2011-01-01

    Full Text Available Evidence from clinical trials as well as from studies performed in animal models suggest that both amyloid and tau pathologies function in concert with other factors to cause the severe neurodegeneration and dementia in Alzheimer’s disease (AD patients. Accumulating data in the literature suggest that microRNAs (miRNAs could be such factors. These conserved, small nonprotein-coding RNAs are essential for neuronal function and survival and have been implicated in the regulation of key genes involved in genetic and sporadic AD. The study of miRNA changes in AD mouse models provides an appealing approach to address the cause-consequence relationship between miRNA dysfunction and AD pathology in humans. Mouse models also provide attractive tools to validate miRNA targets in vivo and provide unique platforms to study the role of specific miRNA-dependent gene pathways in disease. Finally, mouse models may be exploited for miRNA diagnostics in the fight against AD.

  20. The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis

    OpenAIRE

    Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Franke, Lude; Golub, Todd R.

    2016-01-01

    Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tu...

  1. Skeletal metastasis: treatments, mouse models,and the Wnt signaling

    Institute of Scientific and Technical Information of China (English)

    Kenneth C.Valkenburg; Matthew R.Steensma; Bart O.Williams; Zhendong Zhong

    2013-01-01

    Skeletal metastases result in significant morbidity and mortality.This is particularly true of cancers with a strong predilection for the bone,such as breast,prostate,and lung cancers.There is currently no reliable cure for skeletal metastasis,and palliative therapy options are limited.The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target.Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments.In this review,we discuss pathologic process of bone metastasis,the roles of the Wnt signaling,and the available experimental models and treatments.

  2. Dietary Zinc and Prostate Cancer in the TRAMP Mouse Model

    OpenAIRE

    Prasad, Ananda S; Mukhtar, Hasan; Beck, Frances W.J.; Adhami, Vaqar M.; Siddiqui, Imtiaz A.; Din, Maria; Hafeez, Bilal B.; KUCUK, Omer

    2010-01-01

    Circumstantial evidence indicates that zinc may have an important role in the prostate. Total zinc levels in the prostate are 10 times higher than in other soft tissues. Zinc concentrations in prostate epithethial cancer cells are decreased significantly. Zinc supplementation for prevention and treatment of prostate cancer in humans has yielded controversial results. No studies have been reported in animal models to show the effect of zinc supplementation on prevention of prostate cancer, thu...

  3. Resveratrol Neuroprotection in a Chronic Mouse Model of Multiple Sclerosis

    OpenAIRE

    Zoe eFonseca-Kelly; Mayssa eNassrallah; Jorge eUribe; Khan, Reas S.; Kimberly eDine; Mahasweta eDutt; Shindler, Kenneth S.

    2012-01-01

    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 st...

  4. A mighty mouse: building a better model of multiple sclerosis

    OpenAIRE

    Ransohoff, Richard M.

    2006-01-01

    The 2 cardinal cell populations mediating adaptive immunity are T and B lymphocytes. These cells play important but poorly understood roles in the immunopathological demyelinating disease multiple sclerosis (MS) and in a widely used animal model of human MS known as EAE. In the current issue of the JCI, 2 research teams report their parallel studies of double-transgenic mice expressing T and B cell receptors that recognize the same myelin protein (see the related articles beginning on pages 2...

  5. A nude mouse model of endometriosis and its biological behaviors

    Institute of Scientific and Technical Information of China (English)

    WANG Dan-bo; ZHANG Shu-lan; NIU Hui-yan; LU Jing-ming

    2005-01-01

    @@ Endometriosis (EM) as a common and intractable gynecological disease is characterized by unknown etiology and complex pathologic changes. Many factors of the disease are uncertain at the molecular level and it is difficult to study clinically. In this study, we attempted to establish a nude mice model of EM for dynamical observation of the genesis and development of the disease, morphological changes in tissue, and biological behaviors.

  6. 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. PMID:27149521

  7. 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.

  8. 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.

  9. Salmonella vaccines: lessons from the mouse model or bad teaching?

    Science.gov (United States)

    Strugnell, Richard A; Scott, Timothy A; Wang, Nancy; Yang, Chenying; Peres, Newton; Bedoui, Sammy; Kupz, Andreas

    2014-02-01

    Salmonella enterica subsp. enterica includes several very important human serovars including Typhi, Paratyphi, Typhimurium and Enteritidis. These bacteria cause a significant global burden of disease, typically classified into enteric fever, gastroenteritis and, more recently, invasive non-typhoidal salmonellosis (iNTS). Vaccines have been developed for one of these serovars, S. Typhi and the recent increase in iNTS cases has resulted in a push to develop new vaccines that will inhibit disease by S. Typhimurium and S. Enteritidis, the most common iNTS S. enterica serovars. The development of new human vaccines has been informed by studies in the murine model of typhoid fever based on S. Typhimurium infections of very 'sensitive' (Nramp-1(S)) mice, which has some obvious deficiencies, not the least that antibodies protect humans against S. Typhi infection but are only weakly protective in 'sensitive' mice infected with S. Typhimurium. S. Typhimurium also lacks Vi, the target of protective antibodies in typhoid fever. Notwithstanding these deficiencies, the murine model has identified a very complex series of innate and adaptive immune responses to infection that might be exploited to develop new vaccines. Equally, advances in understanding the pathogenesis of infection, through pathogenomics and more sophisticated animal models will likely contribute to the development of novel immunogens.

  10. Perinatal Gjb2 gene transfer rescues hearing in a mouse model of hereditary deafness.

    Science.gov (United States)

    Iizuka, Takashi; Kamiya, Kazusaku; Gotoh, Satoru; Sugitani, Yoshinobu; Suzuki, Masaaki; Noda, Tetsuo; Minowa, Osamu; Ikeda, Katsuhisa

    2015-07-01

    Hearing loss is the most widespread sensory disorder, with an incidence of congenital genetic deafness of 1 in 1600 children. For many ethnic populations, the most prevalent form of genetic deafness is caused by recessive mutations in the gene gap junction protein, beta 2, 26 kDa (GJB2), which is also known as connexin 26 (Cx26). Despite this knowledge, existing treatment strategies do not completely recover speech perception. Here we used a gene delivery system to rescue hearing in a mouse model of Gjb2 deletion. Mice lacking Cx26 are characterized by profound deafness from birth and improper development of cochlear cells. Cochlear delivery of Gjb2 using an adeno-associated virus significantly improved the auditory responses and development of the cochlear structure. Using gene replacement to restore hearing in a new mouse model of Gjb2-related deafness may lead to the development of therapies for human hereditary deafness.

  11. 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.

  12. MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Lore Becker

    Full Text Available Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1 were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.

  13. 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.

  14. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model

    Science.gov (United States)

    Li, Tong; Braunstein, Kerstin E.; Zhang, Juhong; Lau, Ashley; Sibener, Leslie; Deeble, Christopher; Wong, Philip C.

    2016-01-01

    A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau. PMID:27373369

  15. Anti-apoptotic treatment in mouse models of age-related hearing loss

    Institute of Scientific and Technical Information of China (English)

    Fengchan Han; Oumei Wang; Quanxiang Cai

    2016-01-01

    Age-related hearing loss (AHL), or presbycusis, is the most common neurodegenerative disorder and top communication deficit of the aged population. Genetic predisposition is one of the major factors in the development of AHL. Generally, AHL is associated with an age-dependent loss of sensory hair cells, spiral ganglion neurons and stria vascularis cells in the inner ear. Although the mechanisms leading to genetic hearing loss are not completely understood, caspase-family proteases function as important signals in the inner ear pathology. It is now accepted that mouse models are the best tools to study the mechanism of genetic hearing loss or AHL. Here, we provide a brief review of recent studies on hearing improvement in mouse models of AHL by anti-apoptotic treatment.

  16. 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.

  17. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome.

    Science.gov (United States)

    Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J

    2015-05-01

    The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain. PMID:25864922

  18. 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.)

  19. Animal models of melanoma: a somatic cell gene delivery mouse model allows rapid evaluation of genesimplicated in human melanoma%Animal models of melanoma: a somatic cell gene delivery mouse model allows rapid evaluation of genes implicated in human melanoma

    Institute of Scientific and Technical Information of China (English)

    Andrea J. McKinney; Sheri L. Holmen

    2011-01-01

    The increasing incidence and mortality associated with advanced stages of melanoma are cause for concern. Few treatment options are available for advanced melanoma and the 5-year survival rate is less than 15%. Targeted therapies may revolutionize melanoma treatment by providing less toxic and more effective strategies. However, maximizing effectiveness requires further understanding of the molecular alterations that drive tumor formation, progression, and maintenance, as well as elucidating the mechanisms of resistance. Several different genetic alterations identified in human melanoma have been recapitulated in mice. This review outlines recent progress made in the development of mouse models of melanoma and summarizes what these findings reveal about the human disease. We begin with a discussion of traditional models and conclude with the recently developed RCAS/TVA somatic cell gene delivery mouse model of melanoma.

  20. 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....... Transthyretin (TTR) is normally responsible for the transport of thyroid hormones and retinol in the blood and CSF. We found that TTR null mice (TTR(-/-) ) did not show significant differences in cortical infarction 24 h after permanent middle cerebral artery occlusion compared with TTR(+/+) control littermates...

  1. Cumulus-specific genes are transcriptionally silent following somatic cell nuclear transfer in a mouse model*

    OpenAIRE

    Tong, Guo-qing; Heng, Boon-chin; Ng, Soon-chye

    2007-01-01

    This study investigated whether four cumulus-specific genes: follicular stimulating hormone receptor (FSHr), hyaluronan synthase 2 (Has2), prostaglandin synthase 2 (Ptgs2) and steroidogenic acute regulator protein (Star), were correctly reprogrammed to be transcriptionally silent following somatic cell nuclear transfer (SCNT) in a murine model. Cumulus cells of C57×CBA F1 female mouse were injected into enucleated oocytes, followed by activation in 10 µmol/L strontium chloride for 5 h and sub...

  2. Macrophages Play a Key Role in Angiogenesis and Adipogenesis in a Mouse Tissue Engineering Model

    OpenAIRE

    Debels, Heidi; Galea, Laurence; Han, Xiao-Lian; Palmer, Jason; van Rooijen, Nico; Morrison, Wayne; Abberton, Keren

    2013-01-01

    We have previously described a mouse adipose tissue engineering model using a silicon chamber enclosing the superficial epigastric pedicle in a Matrigel based environment. We have shown that when Zymosan, a sterile inflammatory agent, is added to the chamber, angiogenesis and adipogenesis are significantly improved. As Zymosan interacts with toll-like receptors on macrophages, the role of macrophages in new tissue development in the tissue engineering chamber was assessed. Morphological and h...

  3. Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

    OpenAIRE

    Jessica Jen-Chu Wang; Christoph Rau; Rozeta Avetisyan; Shuxun Ren; Romay, Milagros C.; Gabriel Stolin; Ke Wei Gong; Yibin Wang; Lusis, Aldons J.

    2016-01-01

    We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with ...

  4. Characterization of the MeCP2R168X knockin mouse model for Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Eike Wegener

    Full Text Available Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2(R168X mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2(R168X mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging.

  5. Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model

    Science.gov (United States)

    Jung, Yong Gi; Lane, Andrew P.

    2016-01-01

    Objective To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (Etanercept) on an inducible olfactory inflammation (IOI) mouse model Study Design An in vivo study using a transgenic mouse model Setting Research laboratory Subjects and Methods To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis (CRS)-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally-controlled fashion specifically within the olfactory epithelium. In one group of mice (n=4), Etanercept was injected intraperitoneally (100 µg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n=2) underwent induction of TNF-α expression for 8 weeks, with Etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with equal number of control group. Results Compared to non-treated IOI mice, Etanercept -treated IOI mice showed significantly improved EOG responses after 2 weeks (p<0.001). After 8 weeks of induced inflammation, there was massive loss of olfactory epithelium and no EOG response in non-treated IOI mice. However, in Etanercept - treated mice, regeneration of olfactory epithelium was observed. Conclusion Concomitant administration of Etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that Etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models. PMID:26932943

  6. Establishment of Orthotopic Xuanwei Lung Cancer SCID Mouse Model 
and Analysis of Biological Properties

    OpenAIRE

    Yongchun ZHOU; Chen, Yan; Xicai WANG; Liu, Xin; Hutao SHI; Yao, Qian; Jin, Congguo; Wu, Zhiping; Huang, Yunchao

    2012-01-01

    Background and objective The incidence of Xuanwei lung cancer ranks first in China, and its pathogenesis requires in-depth investigation. This study aims to establish an orthotopic Xuanwei lung cancer severe combined immunodeficiency (SCID) mouse model and to provide a basic experimental platform for further study. Methods The Xuanwei lung cancer cell line XWLC-05 was inoculated into the lung tissue of SCID mice in high and low doses. The tumor formation rates, tumor characteristics, spontane...

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

    Directory of Open Access Journals (Sweden)

    Albee Messing

    2013-03-01

    Full Text Available 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.

  8. Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model

    OpenAIRE

    Santos Verdaguer, M??nica; D'Amico, Davide; Spadoni, Omella; Amador Arjona, Alejandro; Stork, Oliver; Dierssen, Mara

    2013-01-01

    Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our ...

  9. Effects of Raphani Semen on Immuno-response in the Mouse Model of allergi Asthma

    OpenAIRE

    Jai-Young, Park; Ki-Chul, Park; Hee-Soo,Park

    2002-01-01

    Objective: This study was eanied out to investigate the effects of Raphani Semen on immuno-response in the mouse model of allergic asthma. Methods: In this study, BALB/C mice were divided into 6 groups: Normal (Non-treated group), Control (Group with not treated after allergic sensitization and induction by ovalbumin), Treat I (Group with the oral administration of saline after allergic sensitization and induction by ovalbumin), Treat n (Allergic asthma group treated with acupuncture (BL ...

  10. PATHOPHYSIOLOGIC BASIS OF LIVER DISEASE IN CYSTIC FIBROSIS EMPLOYING A ΔF508 MOUSE MODEL

    OpenAIRE

    Freudenberg, Folke; BRODERICK, ANNEMARIE L.; Yu, Bian B.; Leonard, Monika R.; Glickman, Jonathan N.; CAREY, MARTIN C.

    2008-01-01

    The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiologic manifestations employing a mouse model carrying ΔF508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, this should lead to a hydrophobic bile salt profile and to “hyperbilirubinbilia” because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then...

  11. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells

    OpenAIRE

    Arnold, I C; Dehzad, N; Reuter, S; Martin, H.; Becher, B; Taube, C.; Müller, A.

    2011-01-01

    Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correla...

  12. Assessing the validity of current mouse genetic models of obsessive–compulsive disorder

    OpenAIRE

    Wang, Li; Simpson, Helen B.; Dulawa, Stephanie C.

    2009-01-01

    Obsessive–compulsive disorder (OCD) is a disorder characterized by unwanted and intrusive thoughts, images, or impulses and/or repetitive behavior. OCD is a major cause of disability; however, the genetic factors and pathophysiological mechanisms underlying this complex, heterogeneous disorder remain largely unknown. During the past decade, a number of putative mouse genetic models of OCD have been developed for the purpose of studying the neural mechanisms underlying this disorder and develo...

  13. Modulation of Lupus Phenotype by Adiponectin Deficiency in Autoimmune Mouse Models

    OpenAIRE

    Parker, Jennifer; Menn-Josephy, Hanni; Laskow, Bari; Takemura, Yukihiro; Aprahamian, Tamar

    2010-01-01

    Adiponectin is an adipocyte-derived cytokine with anti-inflammatory properties. Paradoxically, circulating adiponectin levels are increased in a number of inflammatory diseases. Thus, we sought to define the role of adiponectin deficiency in mouse models of autoimmunity. Adiponectin-deficient mice on a C57BL/6 background do not develop an autoimmune phenotype. Autoimmunity was also not observed in adiponectin-deficient mice generated on the permissive MRL background. However, adiponectin defi...

  14. Genomic analysis to define molecular basis of aggressiveness in a mouse model of oral cancer

    OpenAIRE

    Varun Chalivendra; Krishna Latha Kanchi; Onken, Michael D.; Ashley E. Winkler; Elaine Mardis; Ravindra Uppaluri

    2014-01-01

    To investigate the molecular basis underlying aggressive behavior in oral squamous cell carcinoma (OSCC), our laboratory developed a carcinogen-induced mouse oral cancer (MOC) cell line model that encompasses the growth and metastasis spectrum of its human counterpart. We performed next-generation sequencing (NGS) and gene expression microarray profiles to explore the genomic and transcriptional backgrounds of the differential MOC line phenotypes, as well as, the cross-species relevance of th...

  15. Core modular blood and brain biomarkers in social defeat mouse model for post traumatic stress disorder

    OpenAIRE

    Yang, Ruoting; Daigle Jr, Bernie J; Muhie, Seid Y; Hammamieh, Rasha; Jett, Marti; Petzold, Linda; Francis J Doyle

    2013-01-01

    Abstract Background Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects a substantial portion of combat veterans and poses serious consequences to long-term health. Consequently, the identification of diagnostic and prognostic blood biomarkers for PTSD is of great interest. Previously, we assessed genome-wide gene expression of seven brain regions and whole blood in a social defeat mouse model subjected to various stress co...

  16. A New Mouse Model for Mania Shares Genetic Correlates with Human Bipolar Disorder

    OpenAIRE

    Michael C Saul; Gessay, Griffin M.; Gammie, Stephen C.

    2012-01-01

    Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments att...

  17. Immunohistochemical and electrophysiological characterization of the mouse model for Retinitis Pigmentosa, rd10

    OpenAIRE

    Biswas, Sonia

    2014-01-01

    In the human disease retinitis pigmentosa (RP) the photoreceptors degenerate over time but the retinal network, in particular the retinal output neurons, the ganglion cells (RGCs) persist, providing a target for electrical stimulation by retinal prostheses. However, remodelling of the retinal network might interfere with this therapeutic approach. In the widely used mouse model of retinal degeneration, rd1, the loss of photoreceptors leads to rhythmic electrical activity of 10 to 16 Hz in the...

  18. Lithium prevents parkinsonian behavioral and striatal phenotypes in an aged parkin mutant transgenic mouse model

    OpenAIRE

    LIEU, CHRISTOPHER A.; Dewey, Colleen M.; Chinta, Shankar J.; Rane, Anand; Rajagopalan, Subramanian; Batir, Sean; Kim, Yong-Hwan; Julie K. Andersen

    2014-01-01

    Lithium has long been used as a treatment for the psychiatric disease bipolar disorder. However, previous studies suggest that lithium provides neuroprotective effects in neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease. The exact mechanism by which lithium exerts these effects still remains unclear. In the present study, we evaluated the effects of low-dose lithium treatment in an aged mouse model expressing a parkin mutation within dopaminergic neurons. We...

  19. A Non-Anesthetized Mouse Model for Recording Sensory Urinary Bladder Activity

    OpenAIRE

    Peter Zvara; Wright, Andrew J.; Kristopher Roach; Michal Ursiny; Bennett Shapiro; Dagrosa, Lawrence M.; Nelson, Mark T.; Heppner, Thomas J.

    2010-01-01

    The goal of this study was to develop an in vivo awake mouse model for extracellular bladder sensory nerve recording. A bipolar 125-µm silver electrode was positioned under a single postganglionic bladder nerve. Efferent nerve signals were eliminated by tying off the postganglionic bladder nerve between the major pelvic ganglion and the recording electrode. Sensory nerve activity was measured in the conscious animals 48 hours after surgery during continuous intravesical infusion of 0.9...

  20. Recent Technological Advances in Using Mouse Models to Study Ovarian Cancer

    OpenAIRE

    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 ...

  1. Regulatory T Cells Prevent Liver Fibrosis During HIV Type 1 Infection in a Humanized Mouse Model

    OpenAIRE

    Nunoya, Jun-ichi; Washburn, Michael L.; Kovalev, Grigoriy I; Su, Lishan

    2013-01-01

    Human immunodeficiency virus type 1 (HIV-1) disease is associated with aberrant immune activation, and coinfection with hepatitis C virus (HCV) exacerbates hepatic inflammation and fibrosis. However, the role of HIV-1 infection or host immune modulation in liver pathogenesis is not clearly defined. Here, we report that regulatory T (Treg) cells prevent liver immunopathogenesis during HIV-1 infection in a humanized mouse model. In the absence of Treg cells, HIV-1 infection induced liver fibros...

  2. Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis—A Literature Review

    OpenAIRE

    Leena Rivina; Robert Schiestl

    2012-01-01

    As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus) remains one of the best anim...

  3. Gastroprotective effect of Desmodium gangeticum roots on gastric ulcer mouse models

    OpenAIRE

    Ayyavu Mahesh; Robert Jeyachandran; Dowlathabad Muralidhara Rao; Devarajan Thangadurai

    2012-01-01

    In the present study, the ethanolic root extract of Desmodium gangeticum (L.) DC., Fabaceae, (EDG), have been studied in various acute and chronic ulcer mouse models. Oral administration of root extract, significantly decrease the ulcer index and lesion number in a dose dependent manner against ethanol induced acute gastric ulcer in mice. In gastric ulcerated animal that received high dose of 150 mg/kg EDG, the mucosa showed no ulceration with slight focal congestion and the glands appeared n...

  4. An initial top-down proteomic analysis of the standard cuprizone mouse model of multiple sclerosis

    OpenAIRE

    Partridge, Melissa A.; Gopinath, Sumana; Myers, Simon J.; Jens R Coorssen

    2015-01-01

    An initial proteomic analysis of the cuprizone mouse model to characterise the breadth of toxicity by assessing cortex, skeletal muscle, spleen and peripheral blood mononuclear cells. Cuprizone treated vs. control mice for an initial characterisation. Select tissues from each group were pooled, analysed in triplicate using two-dimensional gel electrophoresis (2DE) and deep imaging and altered protein species identified using liquid chromatography tandem mass spectrometry (LC/MS/MS). Forty-thr...

  5. Cellular and molecular neuropathology of the cuprizone mouse model: Clinical relevance for multiple sclerosis

    OpenAIRE

    Praet, Jelle; Guglielmetti, Caroline; Berneman, Zwi; Van der Linden, Annemie; Ponsaerts, Peter

    2014-01-01

    Abstract: The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of cupri...

  6. The primary locus of motor neuron death in an ALS–PDC mouse model

    OpenAIRE

    Lee, Grace; Chu, Tony; Shaw, Christopher A.

    2009-01-01

    A mouse model of amyotrophic lateral sclerosis–parkinsonism–dementia complex based on the consumption of cycad seed flour was used to determine whether the observed pathology of motor neuron loss begins in the distal axons or the spinal cord. Assessments of neuromuscular junction integrity and motor neurons were performed at multiple time points. Mice fed cycad pellets performed worse on the wire hang than controls. Microglial activation in cycad-fed mice was observed with motor neuron degene...

  7. Drinking Citrus Fruit Juice Inhibits Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model

    OpenAIRE

    Ohnishi, Arika; Asayama, Rie; Mogi, Masaki; Nakaoka, Hirotomo; Kan-no, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-01-01

    Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Cit...

  8. Effects of Laminaria japonica polysaccharides on exercise endurance and oxidative stress in forced swimming mouse model

    OpenAIRE

    Yan, Feiwei; Hao, Haitao

    2016-01-01

    Background Polysaccharides are the major active ingredients responsible for the bioactivities of Laminaria japonica. However, the effects of L. japonica polysaccharides (LJP) on exercise endurance and oxidative stress have never been investigated. Therefore, this study was conducted to investigate the effects of LJP on exercise endurance and oxidative stress in a forced swimming mouse model. The animals were divided into four groups, namely the control (C), LJP-75, LJP-150, and LJP-300 groups...

  9. Aerobic Exercise Attenuates Airway Inflammatory Responses in a Mouse Model of Atopic Asthma

    OpenAIRE

    Pastva, Amy; Estell, Kim; Schoeb, Trenton R.; Atkinson, T. Prescott; Schwiebert, Lisa M

    2004-01-01

    Recent reports indicate that aerobic exercise improves the overall physical fitness and health of asthmatic patients. The specific exercise-induced improvements in the pathology of asthma and the mechanisms by which these improvements occur, however, are ill-defined; thus, the therapeutic potential of exercise in the treatment of asthma remains unappreciated. Using an OVA-driven mouse model, we examined the role of aerobic exercise in modulating inflammatory responses associated with atopic a...

  10. 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.

  11. Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

    OpenAIRE

    Ehre, Camille; Worthington, Erin N.; Liesman, Rachael M.; Grubb, Barbara R.; Barbier, Diane; O’Neal, Wanda K; Sallenave, Jean-Michel; Pickles, Raymond J.; Boucher, Richard C.

    2012-01-01

    MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in...

  12. Effect of Retinoic Acid in a Mouse Model of Allergic Rhinitis

    OpenAIRE

    Son, Hye-Lim; Park, Hyang-Rim; Park, Yong-Jin; Kim, Soo-Whan

    2015-01-01

    Purpose All-trans retinoic acid (ATRA) modulates immune responses by affecting T cells. Several studies have revealed that allergic inflammation of the lower airways is negatively associated with the vitamin A concentration. However, the role of ATRA in allergic inflammation of the upper airways is unclear. We investigated the effects of ATRA in an allergic rhinitis mouse model. Methods BALB/c mice except control groups (CON group) were sensitized with and challenged intra-nasally with Dermat...

  13. The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease

    OpenAIRE

    Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H.; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M.; Gross, Adam K; Heusner, Carrie L.; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

    2013-01-01

    Objectives There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in ...

  14. Modifications of retinal neurons in a mouse model of retinitis pigmentosa

    OpenAIRE

    Strettoi, Enrica; Pignatelli, Vincenzo

    2000-01-01

    Animal models of retinitis pigmentosa include the rd mouse, in which a mutation of a rod-specific phosphodiesterase leads to the rapid loss of photoreceptors during the early postnatal life. Very little is known about changes occurring in inner retinal neurons after photoreceptor loss. These changes are important in view of the possibility of restoring vision in retinas with photoreceptor degeneration by means of cell transplantation or direct stimulation of inner ...

  15. A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism.

    OpenAIRE

    Alicja ePuścian; Szymon eŁęski; Tomasz eGórkiewicz; Ksenia eMeyza; Hans-Peter eLipp; Ewelina Anna Knapska

    2014-01-01

    Repetitive behaviors are a key feature of many pervasive developmental disorders, such as autism. As a heterogeneous group of symptoms, repetitive behaviors are conceptualized into two main subgroups: sensory/motor (lower-order) and cognitive rigidity (higher-order). Although lower-order repetitive behaviors are measured in mouse models in several paradigms, so far there have been no high-throughput tests directly measuring cognitive rigidity. We describe a novel approach for monitoring repet...

  16. BAFF Blockade Prevents Anti-Drug Antibody Formation in a Mouse Model of Pompe Disease

    OpenAIRE

    Doerfler, Phillip A.; Nayak, Sushrusha; Herzog, Roland W; Morel, Laurence; Barry J Byrne

    2015-01-01

    Antibodies formed against the therapeutic protein are a life-threatening complication that arises during enzyme replacement therapy for Pompe disease (acid α-glucosidase deficiency; GAA). To provide an effective alternative to current practices, we investigated the capacity of anti-B-cell activating factor (BAFF) as a novel drug candidate to prevent antibody formation in a Pompe disease mouse model. A BAFF-neutralizing antibody was administered prophylactically and with maintenance doses in a...

  17. Proteomic profiling of the hypothalamus in a mouse model of cancer-induced anorexia-cachexia

    OpenAIRE

    Ihnatko, Robert; Post, Claes; Blomqvist, Anders

    2013-01-01

    Background: Anorexia-cachexia is a common and severe cancer-related complication but the underlying mechanisms are largely unknown. Here, using a mouse model for tumour-induced anorexia-cachexia, we screened for proteins that are differentially expressed in the hypothalamus, the brain’s metabolic control centre. Methods: The hypothalamus of tumour-bearing mice with implanted methylcholanthrene-induced sarcoma (MCG 101) displaying anorexia and their sham-implanted pair-fed or free-fed litterma...

  18. Antibiotic Selection of Escherichia coli Sequence Type 131 in a Mouse Intestinal Colonization Model

    OpenAIRE

    Boetius Hertz, Frederik; Løbner-Olesen, Anders; Frimodt-Møller, Niels

    2014-01-01

    The ability of different antibiotics to select for extended-spectrum β-lactamase (ESBL)-producing Escherichia coli remains a topic of discussion. In a mouse intestinal colonization model, we evaluated the selective abilities of nine common antimicrobials (cefotaxime, cefuroxime, dicloxacillin, clindamycin, penicillin, ampicillin, meropenem, ciprofloxacin, and amdinocillin) against a CTX-M-15-producing E. coli sequence type 131 (ST131) isolate with a fluoroquinolone resistance phenotype. Mice ...

  19. Magnetic Nanoparticle-Based Hyperthermia for Head & Neck Cancer in Mouse Models

    OpenAIRE

    Zhao, Qun; Wang, Luning; Cheng, Rui; Mao, Leidong; Arnold, Robert D.; Howerth, Elizabeth W.; Chen, Zhuo G; Platt, Simon

    2012-01-01

    In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line). A hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields. Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect. Experimental results showed that the temperature of the tumor center has dramatically...

  20. Deregulated Lipid Sensing by Intestinal CD36 in Diet-Induced Hyperinsulinemic Obese Mouse Model

    OpenAIRE

    Marjorie Buttet; Hélène Poirier; Véronique Traynard; Kévin Gaire; Thi Thu Trang Tran; Sinju Sundaresan; Philippe Besnard; Abumrad, Nada A.; Isabelle Niot

    2016-01-01

    The metabolic syndrome (MetS) greatly increases risk of cardiovascular disease and diabetes and is generally associated with abnormally elevated postprandial triglyceride levels. We evaluated intestinal synthesis of triglyceride-rich lipoproteins (TRL) in a mouse model of the MetS obtained by feeding a palm oil-rich high fat diet (HFD). By contrast to control mice, MetS mice secreted two populations of TRL. If the smaller size population represented 44% of total particles in the beginning of ...

  1. Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

    OpenAIRE

    Qifeng Zhou; Scott Kesteven; Jianxin Wu; Parwez Aidery; Meinrad Gawaz; Michael Gramlich; Feneley, Michael P.; Harvey, Richard P.

    2015-01-01

    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 t...

  2. 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 ...

  3. Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex

    OpenAIRE

    Cohn, Ronald D.; Durbeej, Madeleine; Moore, Steven A.; Coral-Vazquez, Ramón; Prouty, Sally; Campbell, Kevin P.

    2001-01-01

    Cardiomyopathy is a multifactorial disease, and the dystrophin-glycoprotein complex has been implicated in the pathogenesis of both hereditary and acquired forms of the disease. Using mouse models of cardiomyopathy made by ablating genes for components of the sarcoglycan complex, we show that long-term treatment with verapamil, a calcium channel blocker with vasodilator properties, can alleviate the severe cardiomyopathic phenotype, restoring normal serum levels for cardiac troponin I and nor...

  4. A commentary on the utility of a new L-DOPA-responsive dystonia mouse model.

    Science.gov (United States)

    Rose, Samuel J; Hess, Ellen J

    2016-01-01

    In a recent issue of Brain, we reported on the generation and characterization of a mouse model of the rare disease L-DOPA-responsive dystonia (DRD). Here, we discuss the utility of these mice for understanding broader disease processes and treatment strategies. Using specific experimental designs that either work "forward" from genetic etiology or "backward" from the symptomatic presentation, we discuss how our data and future work can be used to understand broader themes. PMID:27141408

  5. Toxocara in the mouse : A model for parasite-altered host behaviour ?

    OpenAIRE

    Holland, Celia

    2001-01-01

    The objective of this paper is to critically evaluate the significance of parasite-altered host behaviour in the Toxocara mouse model particularly in the light of the Manipulation Hypothesis. Murine behaviours were examined in both outbred and inbred strains of mice infected with different doses of Toxocara canis ova. Behaviours investigated included activity, exploration, response to novelty, anxiety, learning, memory and social behaviour. Subsequent modifications to the behaviour of infecte...

  6. MOUSE MODEL FOR PRE-CLINICAL STUDY OF HUMAN CANCER IMMUNOTHERAPY

    OpenAIRE

    Ya, Zhiya; Hailemichael, Yared; Overwijk, Willem; Restifo, Nicholas

    2015-01-01

    This unit describes protocols for developing tumors in mice including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modif...

  7. Proteomic profiling of lymphedema development in mouse model.

    Science.gov (United States)

    Lee, Joomin; Song, Haeun; Roh, Kangsan; Cho, Sungrae; Lee, Sukchan; Yeom, Chang-Hwan; Park, Seyeon

    2016-07-01

    The lymphatic vascular system plays an important role in tissue fluid homeostasis. Lymphedema is a chronic, progressive, and incurable condition that leads to lymphatic fluid retention; it may be primary (heritable) or secondary (acquired) in nature. Although there is a growing understanding of lymphedema, methods for the prevention and treatment of lymphedema are still limited. In this study, we investigated differential protein expressions in sham-operated and lymphedema-operated mice for 3 days, using two-dimensional gel electrophoresis (2-DE) and mass spectrometry analysis. Male improved methodology for culturing noninbred (ICR) mice developed lymphedema in the right hindlimb. Twenty functional proteins were found to be differentially expressed between lymphedema induced-right leg tissue and normal left leg tissue. Out of these proteins, the protein levels of apolipoprotein A-1 preprotein, alpha-actinin-3, mCG21744, parkinson disease, serum amyloid P-component precursor, annexin A8, mKIAA0098 protein, and fibrinogen beta chain precursor were differentially upregulated in the lymphedema mice compared with the sham-operated group. Western blotting analysis was used to validate the proteomics results. Our results showing differential up-regulation of serum amyloid P-component precursor, parkinson disease, and apolipoprotein A-1 preprotein in lymphedema model over sham-operated model suggest important insights into pathophysiological target for lymphedema. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27151289

  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. Mouse Models of Diabetes, Obesity and Related Kidney Disease

    Science.gov (United States)

    Glastras, Sarah J.; Chen, Hui; Teh, Rachel; McGrath, Rachel T.; Chen, Jason; Pollock, Carol A.; Wong, Muh Geot; Saad, Sonia

    2016-01-01

    Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice. PMID:27579698

  10. Mouse Models of Diabetes, Obesity and Related Kidney Disease.

    Science.gov (United States)

    Glastras, Sarah J; Chen, Hui; Teh, Rachel; McGrath, Rachel T; Chen, Jason; Pollock, Carol A; Wong, Muh Geot; Saad, Sonia

    2016-01-01

    Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice. PMID:27579698

  11. 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

  12. 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.

  13. New Mouse Models to Investigate the Efficacy of Drug Combinations in Human Chronic Myeloid Leukemia.

    Science.gov (United States)

    Lin, Hanyang; Woolfson, Adrian; Jiang, Xiaoyan

    2016-01-01

    Chronic myeloid leukemia (CML) comprises a simple and effective paradigm for generating new insights into the cellular origin, pathogenesis, and treatment of many types of human cancer. In particular, mouse models of CML have greatly facilitated the understanding of the underlying molecular mechanisms and pathogenesis of this disease and have led to the identification of new drug targets that in some cases offer the possibility of functional cure. There are currently three established CML mouse models: the BCR-ABL transgenic model, the BCR-ABL retroviral transduction/transplantation model, and the xenotransplant immunodeficient model. Each has its own unique advantages and disadvantages. Depending on the question of interest, some models may be more appropriate than others. In this chapter, we describe a newly developed xenotransplant mouse model to determine the efficacy of novel therapeutic agents, either alone or in combination. The model facilitates the evaluation of the frequency of leukemic stem cells with long-term leukemia-initiating activity, a critical subcellular population that causes disease relapse and progression, through the utilization of primary CD34(+) CML stem/progenitor cells obtained from CML patients at diagnosis and prior to drug treatment. We have also investigated the effectiveness of new combination treatment strategies designed to prevent the development of leukemia in vivo using BCR-ABL (+) blast crisis cells as a model system. These types of in vivo studies are important for the prediction of individual patient responses to drug therapy, and have the potential to facilitate the design of personalized combination therapy strategies. PMID:27581149

  14. Electroporative transfection with KGF-1 DNA improves wound healing in a diabetic mouse model.

    Science.gov (United States)

    Marti, G; Ferguson, M; Wang, J; Byrnes, C; Dieb, R; Qaiser, R; Bonde, P; Duncan, M D; Harmon, J W

    2004-12-01

    We recently demonstrated that electroporation enhances transfection in a mouse wound-healing model. Keratinocyte growth factor (KGF) is an inducer of epithelial cell proliferation and differentiation and has been shown to be under expressed in the wounds of diabetic individuals. We hypothesized that KGF delivered into an excisional wound via naked DNA injection with subsequent electroporation would be a novel and potentially effective method to enhance wound closure in a diabetic mouse model. ELISA assays confirmed production of KGF protein in cultured mouse cells and RT-PCR assays confirmed KGF mRNA in skin samples taken from mice. In all, 32 genetically diabetic mice were given two identical excisional wounds of their dorsum and split into two groups with one group receiving KGF DNA injection and electroporation with the other group receiving no treatment. Over 90% of wounds healed in the presence of KGF and electroporation versus 40% in the untreated group by day 12. Histological analysis of the wounds demonstrated that untreated wounds contained microulcers with thin or incomplete epithelium with unresolved inflammation as compared to treated wounds where intact and mature epithelium was observed. Taken together these findings suggest that a single injection of KGF DNA encoded on a plasmid coupled with electroporation improves and accelerates wound closure in a delayed wound-healing model.

  15. Mouse models of liver fibrosis mimic human liver fibrosis of different etiologies.

    Science.gov (United States)

    Martínez, Allyson K; Maroni, Luca; Marzioni, Marco; Ahmed, Syed T; Milad, Mena; Ray, Debolina; Alpini, Gianfranco; Glaser, Shannon S

    2014-12-01

    The liver has the amazing capacity to repair itself after injury; however, the same processes that are involved in liver regeneration after acute injury can cause serious consequences during chronic liver injury. In an effort to repair damage, activated hepatic stellate cells trigger a cascade of events that lead to deposition and accumulation of extracellular matrix components causing the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis. Although fibrosis occurs as a result of many chronic liver diseases, the molecular mechanisms involved depend on the underlying etiology. Since studying liver fibrosis in human subjects is complicated by many factors, mouse models of liver fibrosis that mimic the human conditions fill this void. This review summarizes the general mouse models of liver fibrosis and mouse models that mimic specific human disease conditions that result in liver fibrosis. Additionally, recent progress that has been made in understanding the molecular mechanisms involved in the fibrogenic processes of each of the human disease conditions is highlighted. PMID:25396098

  16. Application of mouse model for effective evaluation of foot-and-mouth disease vaccine.

    Science.gov (United States)

    Lee, Seo-Yong; Ko, Mi-Kyeong; Lee, Kwang-Nyeong; Choi, Joo-Hyung; You, Su-Hwa; Pyo, Hyun-Mi; Lee, Myoung-Heon; Kim, Byounghan; Lee, Jong-Soo; Park, Jong-Hyeon

    2016-07-19

    Efficacy evaluation of foot-and-mouth disease (FMD) vaccines has been conducted in target animals such as cows and pigs. In particular, handling FMD virus requires a high level of biosafety management and facilities to contain the virulent viruses. The lack of a laboratory animal model has resulted in inconvenience when it comes to using target animals for vaccine evaluation, bringing about increased cost, time and labor for the experiments. The FMD mouse model has been studied, but most FMD virus (FMDV) strains are not known to cause disease in adult mice. In the present study, we created a series of challenge viruses that are lethal to adult C57BL/6 mice. FMDV types O, A, and Asia1, which are related to frequent FMD outbreaks, were adapted for mice and the pathogenesis of each virus was evaluated in the mouse model. Challenge experiments after vaccination using in-house and commercial vaccines demonstrated vaccine-mediated protection in a dose-dependent manner. In conclusion, we propose that FMD vaccine evaluation should be carried out using mouse-adapted challenge viruses as a swift, effective efficacy test of experimental or commercial vaccines. PMID:27340094

  17. 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.

  18. Effect of Endostar Combined with Gemcitabine on the Mouse Model of Human Pancreatic Cancer

    Institute of Scientific and Technical Information of China (English)

    林清风

    2007-01-01

    Objective To investigate the effects of recombinant human endostatin,that is,endostar combined with gemcitabine on the mouse model of human pancreatic cancer.Methods We use the cell line PANC-1 and the severe combined immune deficient mice to set up the mouse model of human pancreatic cancer,then devide them into three groups,treat them with gemcitabine,gemcitabine combined with endostar,and 0.9% saline water respectively.We observe the change of the tumor volumn,use ELISA method to detect the serum VEGF level,stain the micro vessel in the tumor tissue with immunohistochemistry method,and compare the data among the different groups respectively.Results On the twenty-eighth day,the tumor volume of the control group,the monotherapy group and the combination group,averaged 1 700 mm3,19.2 mm3,10.4 mm3,serum VEGF level 88.6 L,35.5,26.3 pg/mL and MVD 43.9,30.3,19.2 respectively,which had significant difference.Conclusion Endostar can strengthen the lethal effect of gemcitabine on the mouse model of human pancreatic cancer.

  19. Image Analysis-Based Approaches for Scoring Mouse Models of Colitis.

    Science.gov (United States)

    Rogers, R; Eastham-Anderson, J; DeVoss, J; Lesch, J; Yan, D; Xu, M; Solon, M; Hotzel, K; Diehl, L; Webster, J D

    2016-01-01

    Mouse models of inflammatory bowel disease are critical for basic and translational research that is advancing the understanding and treatment of this disease. Assessment of these mouse models frequently relies on histologic endpoints. In recent years, whole slide imaging and digital pathology-based image analysis platforms have become increasingly available for implementation into the pathology workflow. These automated image analysis approaches allow for nonbiased quantitative assessment of histologic endpoints. In this study, the authors sought to develop an image analysis workflow using a commercially available image analysis platform that requires minimal training in image analysis or programming, and this workflow was used to score 2 mouse models of colitis that are primarily characterized by immune cell infiltrates in the lamina propria. Although the software was unable to accurately and consistently segment hematoxylin and eosin-stained sections, automated quantification of CD3 immunolabeling resulted in strong correlations with the pathologist's score in all studies and allowed for the identification of 8 of the 9 differences among treatment groups that were identified by the pathologist. These results demonstrate not only the ability to incorporate solutions based on image analysis into the pathologist's workflow but also the importance of immunohistochemical or histochemical surrogates for the incorporation of image analysis in histologic assessments. PMID:25907770

  20. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  1. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  2. 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

    2016-09-01

    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. PMID:27567836

  3. 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

    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.

  4. Atmosphere behavior in gas-closed mouse-algal systems - An experimental and modelling study

    Science.gov (United States)

    Averner, M. M.; Moore, B., III; Bartholomew, I.; Wharton, R.

    1984-01-01

    A NASA-sponsored research program initiated using mathematical modelling and laboratory experimentation aimed at examining the gas-exchange characteristics of artificial animal/plant systems closed to the ambient atmosphere is studied. The development of control techniques and management strategies for maintaining the atmospheric levels of carbon dioxide and oxygen at physiological levels is considered. A mathematical model simulating the behavior of a gas-closed mouse-algal system under varying environmental conditions is described. To verify and validate the model simulations, an analytical system with which algal growth and gas exchange characteristics can be manipulated and measured is designed, fabricated, and tested. The preliminary results are presented.

  5. Utilizing Past and Present Mouse Systems to Engineer More Relevant Pancreatic Cancer Models

    Directory of Open Access Journals (Sweden)

    Brian T DeCant

    2014-12-01

    Full Text Available The study of pancreatic cancer has prompted the development of numerous mouse models that aim to recapitulate the phenotypic and mechanistic features of this deadly malignancy. This review accomplishes two tasks. First, it provides an overview of the models that have been used as representations of both the neoplastic and carcinoma phenotypes. Second, it presents new modeling schemes that ultimately will serve to more faithfully capture the temporal and spatial progression of the human disease, providing platforms for improved understanding of the role of non-epithelial compartments in disease etiology as well as evaluating therapeutic approaches.

  6. Metabolic profiles of dystrophin and utrophin expression in mouse models of Duchenne muscular dystrophy.

    Science.gov (United States)

    Griffin, J L; Sang, E; Evens, T; Davies, K; Clarke, K

    2002-10-23

    Metabolic profiles from (1)H nuclear magnetic resonance spectroscopy have been used to describe both one and two protein systems in four mouse models related to Duchenne muscular dystrophy using the pattern recognition technique partial least squares. Robust statistical models were built for extracts and intact cardiac tissue, distinguishing mice according to expression of dystrophin. Using metabolic profiles of diaphragm, models were built describing dystrophin and utrophin, a dystrophin related protein, expression. Increased utrophin expression counteracted some of the deficits associated with dystrophic tissue. This suggests the method may be ideal for following treatment regimes such as gene therapy. PMID:12387876

  7. Glyburide reduces bacterial dissemination in a mouse model of melioidosis.

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    Gavin C K W Koh

    Full Text Available BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

  8. Mouse model of sublethal and lethal intraperitoneal glanders (Burkholderia mallei).

    Science.gov (United States)

    Fritz, D L; Vogel, P; Brown, D R; Deshazer, D; Waag, D M

    2000-11-01

    Sixty male BALB/c mice were inoculated intraperitoneally with either a sublethal or a lethal dose of Burkholderia mallei China 7 strain, then killed at multiple time points postinoculation. Histopathologic changes were qualitatively similar in both groups and consisted of pyogranulomatous inflammation. In sublethal study mice, changes were first seen at 6 hours in mediastinal lymph nodes, then in spleen, liver, peripheral lymph nodes, and bone marrow at day 3. These changes generally reached maximal incidence and severity by day 4 but decreased by comparison in all tissues except the liver. Changes were first seen in lethal study mice also at 6 hours in mediastinal lymph nodes and in spleens. At day 1, changes were present in liver, peripheral lymph nodes, and bone marrow. The incidence and severity of these changes were maximal at day 2. In contrast to sublethal study mice, the incidence and severity of the changes did not decrease through the remainder of the study. The most significant difference between the two groups was the rapid involvement of the spleen in the lethal study mice. Changes indicative of impaired vascular perfusion were more frequently seen in the sublethal study mice. Our findings indicate that mice are susceptible to B. mallei infection and may serve as an appropriate model for glanders infection in a resistant host such as human beings. Additionally, by immunoelectron microscopy, we showed the presence of type I O-antigenic polysaccharide (capsular) antigen surrounding B. mallei.

  9. Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model.

    Science.gov (United States)

    Tang, Manshu; Siddiqi, Anwer; Witt, Benjamin; Yuzyuk, Tatiana; Johnson, Britt; Fraser, Nisa; Chen, Wyman; Rascon, Rafael; Yin, Xue; Goli, Harish; Bodamer, Olaf A; Lai, Kent

    2014-10-01

    The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT gene-trapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P=0.02) and longer time-to-pregnancy (P=0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P=0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies. PMID:24549051

  10. 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.

  11. The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis

    OpenAIRE

    Ding, Di; Enriquez-Algeciras, Mabel; Dave, Kunjan R; Perez-Pinzon, Miguel; Bhattacharya, Sanjoy K.

    2012-01-01

    Bhattacharya and collaborators find that a mouse model for multiple sclerosis develops mitochondrial dysfunction through deimination of REF, an RNA-binding protein involved in mRNA transport into mitochondria.

  12. Characterization of a Mouse Model of Oral Potassium Cyanide Intoxication.

    Science.gov (United States)

    Sabourin, Patrick J; Kobs, Christina L; Gibbs, Seth T; Hong, Peter; Matthews, Claire M; Patton, Kristen M; Sabourin, Carol L; Wakayama, Edgar J

    2016-09-01

    Potassium cyanide (KCN) is an inhibitor of cytochrome C oxidase causing rapid death due to hypoxia. A well-characterized model of oral KCN intoxication is needed to test new therapeutics under the Food and Drug Administration Animal Rule. Clinical signs, plasma pH and lactate concentrations, biomarkers, histopathology, and cyanide and thiocyanate toxicokinetics were used to characterize the pathology of KCN intoxication in adult and juvenile mice. The acute oral LD50s were determined to be 11.8, 11.0, 10.9, and 9.9 mg/kg in water for adult male, adult female, juvenile male, and juvenile female mice, respectively. The time to death was rapid and dose dependent; juvenile mice had a shorter mean time to death. Juvenile mice displayed a more rapid onset and higher incidence of seizures. The time to observance of respiratory signs and prostration was rapid, but mice surviving beyond 2 hours generally recovered fully within 8 hours. At doses up to the LD50, there were no gross necropsy or microscopic findings clearly attributed to administration of KCN in juvenile or adult CD-1 mice from 24 hours to 28 days post-KCN challenge. Toxicokinetic analysis indicated rapid uptake, metabolism, and clearance of plasma cyanide. Potassium cyanide caused a rapid, dose-related decrease in blood pH and increase in serum lactate concentration. An increase in fatty acid-binding protein 3 was observed at 11.5 mg/kg KCN in adult but not in juvenile mice. These studies provide a characterization of KCN intoxication in adult and juvenile mice that can be used to screen or conduct preclinical efficacy studies of potential countermeasures.

  13. 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.

  14. Transgenic Mouse Model for Reducing Oxidative Damage in Bone

    Science.gov (United States)

    Schreurs, A.-S.; Torres, S.; Truong, T.; Kumar, A.; Alwood, J. S.; Limoli, C. L.; Globus, R. K.

    2014-01-01

    parameters. Taken together, this typically catabolic treatment (disuse and irradiation) appeared to stimulate cortical expansion in MCAT mice but not WT mice. In conclusion, these results reveal the importance of mitochondrial ROS generation in skeletal remodeling and show that MCAT mice provide a useful animal model for bone studies.

  15. Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD).

    Science.gov (United States)

    Ng, Adeline H; Willett, Thomas L; Alman, Benjamin A; Grynpas, Marc D

    2014-11-01

    The etiology of Adynamic Bone Disease (ABD) is poorly understood but the hallmark of ABD is a lack of bone turnover. ABD occurs in renal osteodystrophy (ROD) and is suspected to occur in elderly patients on long-term anti-resorptive therapy. A major clinical concern of ABD is diminished bone quality and an increased fracture risk. To our knowledge, experimental animal models for ABD other than ROD-ABD have not been developed or studied. The objectives of this study were to develop a mouse model of ABD without the complications of renal ablation, and to characterize changes in bone quality in ABD relative to controls. To re-create the adynamic bone condition, 4-month old female Col2.3Δtk mice were treated with ganciclovir to specifically ablate osteoblasts, and pamidronate was used to inhibit osteoclastic resorption. Four groups of animals were used to characterize bone quality in ABD: Normal bone controls, No Formation controls, No Resorption controls, and an Adynamic group. After a 6-week treatment period, the animals were sacrificed and the bones were harvested for analyses. Bone quality assessments were conducted using established techniques including bone histology, quantitative backscattered electron imaging (qBEI), dual energy X-ray absorptiometry (DXA), microcomputed tomography (microCT), and biomechanical testing. Histomorphometry confirmed osteoblast-related hallmarks of ABD in our mouse model. Bone formation was near complete suppression in the No Formation and Adynamic specimens. Inhibition of bone resorption in the Adynamic group was confirmed by tartrate-resistant acid phosphatase (TRAP) stain. Normal bone mineral density and architecture were maintained in the Adynamic group, whereas the No Formation group showed a reduction in bone mineral content and trabecular thickness relative to the Adynamic group. As expected, the No Formation group had a more hypomineralized profile and the Adynamic group had a higher mean mineralization profile that is

  16. Formation of functional areas in the cerebral cortex is disrupted in a mouse model of autism spectrum disorder

    OpenAIRE

    Fenlon, Laura R; Liu, Sha; Gobius, Ilan; Kurniawan, Nyoman D.; Murphy, Skyle; Moldrich, Randal X.; Linda J Richards

    2015-01-01

    Background Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorders, which have increased in prevalence in the past two decades. Animal models offer the opportunity to understand the biological basis of these disorders. Studies comparing different mouse strains have identified the inbred BTBR T + tf/J (BTBR) strain as a mouse model of ASD based on its anti-social and repetitive behaviours. Adult BTBR mice have complete agenesis of the corpus callosum, reduced cor...

  17. Myocardial contrast echocardiography to assess perfusion in a mouse model of ischemia/reperfusion injury

    Science.gov (United States)

    Hossack, John A.; Li, Yinbo; Christensen, Jonathan P.; Yang, Zequan; French, Brent A.

    2004-04-01

    Noninvasive approaches for measuring anatomical and physiological changes resulting from myocardial ischemia / reperfusion injury in the mouse heart have significant value since the mouse provides a practical, low-cost model for modeling human heart disease. In this work, perfusion was assessed before, during and after an induced closed- chest, coronary ischemic event. Ultrasound contrast agent, similar to MP1950, in a saline suspension, was injected via cannulated carotid artery as a bolus and imaged using a Siemens Sequoia 512 scanner and a 15L8 intraoperative transducer operating in second harmonic imaging mode. Image sequences were transferred from the scanner to a PC for analysis. Regions of interest were defined in septal and anterior segments of the myocardium. During the ischemic event, when perfusion was diminished in the anterior segment, mean video intensity in the affected segment was reduced by one half. Furthermore, following reperfusion, hyperemia (enhanced blood flow) was observed in the anterior segment. Specifically, the mean video intensity in the affected segment was increased by approximately 50% over the original baseline level prior to ischemia. Following the approach of Kaul et al., [1], gamma variate curves were fitted to the time varying level of mean video intensity. This foundation suggests the possibility of quantifying myocardial blood flow in ischemic regions of a mouse heart using automated analysis of contrast image data sets. An improved approach to perfusion assessment using the destruction-reperfusion approach [2] is also presented.

  18. Synaptic Vesicle Recycling Is Unaffected in the Ts65Dn Mouse Model of Down Syndrome.

    Science.gov (United States)

    Marland, Jamie R K; Smillie, Karen J; Cousin, Michael A

    2016-01-01

    Down syndrome (DS) is the most common genetic cause of intellectual disability, and arises from trisomy of human chromosome 21. Accumulating evidence from studies of both DS patient tissue and mouse models has suggested that synaptic dysfunction is a key factor in the disorder. The presence of several genes within the DS trisomy that are either directly or indirectly linked to synaptic vesicle (SV) endocytosis suggested that presynaptic dysfunction could underlie some of these synaptic defects. Therefore we determined whether SV recycling was altered in neurons from the Ts65Dn mouse, the best characterised model of DS to date. We found that SV exocytosis, the size of the SV recycling pool, clathrin-mediated endocytosis, activity-dependent bulk endocytosis and SV generation from bulk endosomes were all unaffected by the presence of the Ts65Dn trisomy. These results were obtained using battery of complementary assays employing genetically-encoded fluorescent reporters of SV cargo trafficking, and fluorescent and morphological assays of fluid-phase uptake in primary neuronal culture. The absence of presynaptic dysfunction in central nerve terminals of the Ts65Dn mouse suggests that future research should focus on the established alterations in excitatory / inhibitory balance as a potential route for future pharmacotherapy.

  19. Synaptic Vesicle Recycling Is Unaffected in the Ts65Dn Mouse Model of Down Syndrome.

    Directory of Open Access Journals (Sweden)

    Jamie R K Marland

    Full Text Available Down syndrome (DS is the most common genetic cause of intellectual disability, and arises from trisomy of human chromosome 21. Accumulating evidence from studies of both DS patient tissue and mouse models has suggested that synaptic dysfunction is a key factor in the disorder. The presence of several genes within the DS trisomy that are either directly or indirectly linked to synaptic vesicle (SV endocytosis suggested that presynaptic dysfunction could underlie some of these synaptic defects. Therefore we determined whether SV recycling was altered in neurons from the Ts65Dn mouse, the best characterised model of DS to date. We found that SV exocytosis, the size of the SV recycling pool, clathrin-mediated endocytosis, activity-dependent bulk endocytosis and SV generation from bulk endosomes were all unaffected by the presence of the Ts65Dn trisomy. These results were obtained using battery of complementary assays employing genetically-encoded fluorescent reporters of SV cargo trafficking, and fluorescent and morphological assays of fluid-phase uptake in primary neuronal culture. The absence of presynaptic dysfunction in central nerve terminals of the Ts65Dn mouse suggests that future research should focus on the established alterations in excitatory / inhibitory balance as a potential route for future pharmacotherapy.

  20. 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

  1. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

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    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.

  2. Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

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    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.

  3. Sex Differences in Circadian Dysfunction in the BACHD Mouse Model of Huntington's Disease.

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    Dika A Kuljis

    Full Text Available Huntington's disease (HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies indicate there may be sex differences in disease progression. One of the early symptoms of HD is disruptions in the circadian timing system, but it is currently unknown whether sex is a factor in these alterations. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s and designing early intervention strategies, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Similar to BACHD males, BACHD females display circadian disruptions at both 3 and 6 months of age; however, deficits to BACHD female mouse activity levels, rhythm precision, and behavioral fragmentation are either delayed or less severe relative to males. These sex differences are associated with a smaller suprachiasmatic nucleus (SCN in BACHD male mice at age of symptom onset (3 months, but are not associated with sex-specific differences in SCN daytime electrical activity deficits, or peptide expression (arginine vasopressin, vasoactive intestinal peptide within the SCN. Notably, BACHD females exhibited delayed motor coordination deficits, as measured using rotarod and challenge beam. These findings suggest a sex specific factor plays a role both in non-motor and motor symptom progression for the BACHD mouse.

  4. Transcranial magnetic stimulation of mouse brain using high-resolution anatomical models

    Science.gov (United States)

    Crowther, L. J.; Hadimani, R. L.; Kanthasamy, A. G.; Jiles, D. C.

    2014-05-01

    Transcranial magnetic stimulation (TMS) offers the possibility of non-invasive treatment of brain disorders in humans. Studies on animals can allow rapid progress of the research including exploring a variety of different treatment conditions. Numerical calculations using animal models are needed to help design suitable TMS coils for use in animal experiments, in particular, to estimate the electric field induced in animal brains. In this paper, we have implemented a high-resolution anatomical MRI-derived mouse model consisting of 50 tissue types to accurately calculate induced electric field in the mouse brain. Magnetic field measurements have been performed on the surface of the coil and compared with the calculations in order to validate the calculated magnetic and induced electric fields in the brain. Results show how the induced electric field is distributed in a mouse brain and allow investigation of how this could be improved for TMS studies using mice. The findings have important implications in further preclinical development of TMS for treatment of human diseases.

  5. Application of Synchrotron Radiation Imaging for Non-destructive Monitoring of Mouse Rheumatoid Arthritis Model

    Science.gov (United States)

    Choi, Chang-Hyuk; Kim, Hong-Tae; Choe, Jung-Yoon; Kim, Jong Ki; Youn, Hwa Shik

    2007-01-01

    This study was performed to observe microstructures of the rheumatoid arthritis induced mouse feet using a synchrotron radiation beam and to compare findings with histological observations. X-ray refraction images from ex-vivo rheumatoid arthritis induced mouse feet were obtained with an 8KeV white (unmonochromatic) beam and 20 micron thick CsI(Tl) scintillation crystal. The visual image was magnified using a × 10 microscope objective and captured using digital CCD camera. Experiments were performed at 1B2 bending magnet beamline of the Pohang Accelerator Laboratory (PAL) in Korea. Obtained images were compared with histopathologic findings from same sample. Cartilage destruction and thickened joint capsule with joint space narrowing were clearly identified at each grade of rheumatoid model with spatial resolution of as much as 1.2 micron and these findings were directly correlated with histopathologic findings. The results suggest that x-ray microscopy study of the rheumatoid arthritis model using synchrotron radiation demonstrates the potential for clinically relevant micro structure of mouse feet without sectioning and fixation.

  6. Studies on the Antifatigue Activities of Cordyceps militaris Fruit Body Extract in Mouse Model.

    Science.gov (United States)

    Song, Jingjing; Wang, Yingwu; Teng, Meiyu; Cai, Guangsheng; Xu, Hongkai; Guo, Hanxiao; Liu, Yang; Wang, Di; Teng, Lesheng

    2015-01-01

    Cordyceps militaris has been used extensively as a crude drug and a folk tonic food in East Asia due to its various pharmacological activities. Our study aims to investigate the effect of Cordyceps militaris fruit body extract (CM) on antifatigue in mouse model. Two week CM administration significantly delayed fatigue phenomenon which is confirmed via rotating rod test, forced swimming test and forced running test. Compared to nontreated mouse, CM administration increased ATP levels and antioxidative enzymes activity and reduced the levels of lactic acid, lactic dehydrogenase, malondialdehyde, and reactive oxygen species. Further data suggests that CM-induced fatigue recovery is mainly through activating 5'-AMP-activated protein kinase (AMPK) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways and regulating serum hormone level. Moreover, CM-enhanced the phosphorylation of AMPK contributes to its antioxidant effect. Our data provides experimental evidence in supporting clinical use of CM as an effective agent against fatigue. PMID:26351509

  7. X-irradiation improves mdx mouse muscle as a model of myofiber loss in DMD

    International Nuclear Information System (INIS)

    The mdx mouse, although a genetic and biochemical homologue of human Duchenne muscular dystrophy (DMD), presents a comparatively mild histopathological and clinical phenotype. These differences are partially attributable to the greater efficacy of regeneration in the mdx mouse than in DMD muscle. To lessen this disparity, we have used a single dose of X-irradiation (16 Gy) to inhibit regeneration in one leg of mdx mice. The result is an almost complete block of muscle fiber regeneration leading to progressive loss of muscle fibers and their replacement by loose connective tissue. Surviving fibers are mainly peripherally nucleated and, surprisingly, of large diameter. Thus, X-irradiation converts mdx muscle to a model system in which the degenerative process can be studied in isolation from the complicating effect of myofiber regeneration. This system should be of use for testing methods of alleviating the myofiber degeneration which is common to mdx and DMD

  8. Analgesic effects of lappaconitine in leukemia bone pain in a mouse model

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    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.

  9. Terahertz spectroscopy of brain tissue from a mouse model of Alzheimer's disease

    Science.gov (United States)

    Shi, Lingyan; Shumyatsky, Pavel; Rodríguez-Contreras, Adrián; Alfano, Robert

    2016-01-01

    The terahertz (THz) absorption and index of refraction of brain tissues from a mouse model of Alzheimer's disease (AD) and a control wild-type (normal) mouse were compared using THz time-domain spectroscopy (THz-TDS). Three dominating absorption peaks associated to torsional-vibrational modes were observed in AD tissue, at about 1.44, 1.8, and 2.114 THz, closer to the peaks of free tryptophan molecules than in normal tissue. A possible reason is that there is more free tryptophan in AD brain tissue, while in normal brain tissue more tryptophan is attached to other molecules. Our study suggests that THz-absorption modes may be used as an AD biomarker fingerprint in brain, and that THz-TDS is a promising technique for early diagnosis of AD.

  10. MOUSE MODEL FOR PRE-CLINICAL STUDY OF HUMAN CANCER IMMUNOTHERAPY

    Science.gov (United States)

    Ya, Zhiya; Hailemichael, Yared; Overwijk, Willem; Restifo, Nicholas

    2015-01-01

    This unit describes protocols for developing tumors in mice including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modification of mouse T cells for adoptive transfer by using retrovirus expressing genes of interest are provided. Additional sections, including growing B16 melanoma, enumerating pulmonary metastases, tumor imaging technique and use of recombinant viruses for vaccination, are discussed together with safety concerns. PMID:25640991

  11. Mouse neuroblastoma cell based model and the effect of epileptic events on calcium oscillations and neural spikes

    Science.gov (United States)

    Kim, Suhwan; Baek, Juyeong; Jung, Unsang; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

    2013-05-01

    Recently, Mouse neuroblastoma cells are considered as an attractive model for the study of human neurological and prion diseases, and intensively used as a model system in different areas. Among those areas, differentiation of neuro2a (N2A) cells, receptor mediated ion current, and glutamate induced physiological response are actively investigated. The reason for the interest to mouse neuroblastoma N2A cells is that they have a fast growing rate than other cells in neural origin with a few another advantages. This study evaluated the calcium oscillations and neural spikes recording of mouse neuroblastoma N2A cells in an epileptic condition. Based on our observation of neural spikes in mouse N2A cell with our proposed imaging modality, we report that mouse neuroblastoma N2A cells can be an important model related to epileptic activity studies. It is concluded that the mouse neuroblastoma N2A cells produce the epileptic spikes in vitro in the same way as produced by the neurons or the astrocytes. This evidence advocates the increased and strong level of neurotransmitters release by enhancement in free calcium using the 4-aminopyridine which causes the mouse neuroblastoma N2A cells to produce the epileptic spikes and calcium oscillation.

  12. 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.

  13. Dmdmdx/Largemyd: a new mouse model of neuromuscular diseases useful for studying physiopathological mechanisms and testing therapies

    Science.gov (United States)

    Martins, Poliana C. M.; Ayub-Guerrieri, Danielle; Martins-Bach, Aurea B.; Onofre-Oliveira, Paula; Malheiros, Jackeline M.; Tannus, Alberto; de Sousa, Paulo L.; Carlier, Pierre G.; Vainzof, Mariz

    2013-01-01

    SUMMARY 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. PMID:23798567

  14. 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.

  15. A genetic mouse model to investigate hyperoxic acute lung injury survival.

    Science.gov (United States)

    Prows, Daniel R; Hafertepen, Amanda P; Gibbons, William J; Winterberg, Abby V; Nick, Todd G

    2007-08-20

    Acute lung injury (ALI) is a devastating disease that maintains a high mortality rate, despite decades of research. Hyperoxia, a universal treatment for ALI and other critically ill patients, can itself cause pulmonary damage, which drastically restricts its therapeutic potential. We stipulate that having the ability to use higher levels of supplemental O2 for longer periods would improve recovery rates. Toward this goal, a mouse model was sought to identify genes contributing to hyperoxic ALI (HALI) mortality. Eighteen inbred mouse strains were screened in continuous >95% O2. A significant survival difference was identified between sensitive C57BL/6J and resistant 129X1/SvJ strains. Although resistant, only one-fourth of 129X1/SvJ mice survived longer than any C57BL/6J mouse, demonstrating decreased penetrance of resistance. A survival time difference between reciprocal F1 mice implicated a parent-of-origin (imprinting) effect. To further evaluate imprinting and begin to delineate the genetic components of HALI survival, we generated and phenotyped offspring from all four possible intercrosses. Segregation analysis supported maternal inheritance of one or more genes but paternal inheritance of one or more contributor genes. A significant sex effect was demonstrated, with males more resistant than females for all F2 crosses. Survival time ranges and sensitive-to-resistant ratios of the different F2 crosses also supported imprinting and predicted that increased survival is due to dominant resistance alleles contributed by both the resistant and sensitive parental strains. HALI survival is multigenic with a complex mode of inheritance, which should be amenable to genetic dissection with this mouse model.

  16. 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.

  17. X-ray phase-contrast CT of a pancreatic ductal adenocarcinoma mouse model.

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    Arne Tapfer

    Full Text Available To explore the potential of grating-based x-ray phase-contrast computed tomography (CT for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i high-resolution synchrotron radiation (SR imaging and ii dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i high-performance imaging for virtual microscopy applications and ii biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR of selected regions of interest (ROI in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.

  18. 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.

  19. An athymic mouse model to mimic cobalt-60 cutaneous radiation injury

    Energy Technology Data Exchange (ETDEWEB)

    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)

  20. Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

    International Nuclear Information System (INIS)

    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

  1. A novel surgical approach for intratracheal administration of bioactive agents in a fetal mouse model.

    Science.gov (United States)

    Carlon, Marianne S; Toelen, Jaan; da Cunha, Marina Mori; Vidović, Dragana; Van der Perren, Anke; Mayer, Steffi; Sbragia, Lourenço; Nuyts, Johan; Himmelreich, Uwe; Debyser, Zeger; Deprest, Jan

    2012-01-01

    Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and acquired diseases. Apart from congenital or inherited abnormalities with the requirement for long-term expression of the delivered gene, several non-inherited perinatal conditions, where short-term gene expression or pharmacological intervention is sufficient to achieve therapeutic effects, are considered as potential future indications for this kind of approach. Candidate diseases for the application of short-term prenatal therapy could be the transient neonatal deficiency of surfactant protein B causing neonatal respiratory distress syndrome(1,2) or hyperoxic injuries of the neonatal lung(3). Candidate diseases for permanent therapeutic correction are Cystic Fibrosis (CF)(4), genetic variants of surfactant deficiencies(5) and α1-antitrypsin deficiency(6). Generally, an important advantage of prenatal gene therapy is the ability to start therapeutic intervention early in development, at or even prior to clinical manifestations in the patient, thus preventing irreparable damage to the individual. In addition, fetal organs have an increased cell proliferation rate as compared to adult organs, which could allow a more efficient gene or stem cell transfer into the fetus. Furthermore, in utero gene delivery is performed when the individual's immune system is not completely mature. Therefore, transplantation of heterologous cells or supplementation of a non-functional or absent protein with a correct version should not cause immune sensitization to the cell, vector or transgene product, which has recently been proven to be the case with both cellular and genetic therapies(7). In the present study, we investigated the potential to directly target the fetal trachea in a mouse model. This procedure is in use in larger animal models such as rabbits and sheep(8), and even in a clinical setting(9), but has to date not been

  2. Physiological and Histological Evaluations of the Cochlea between 3xTg-AD Mouse Model of Alzheimer's Diseases and R6/2 Mouse Model of Huntington's Diseases.

    Science.gov (United States)

    Wang, Sheue-Er; Wu, Chung-Hsin

    2015-12-31

    Patients with Alzheimer's diseases (AD) and Huntington's diseases (HD) are known to have abnormal auditory processing, but the physiological and histological evaluations of the cochlea between AD and HD have not been thoroughly assessed. Thus we assessed the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE), and then examined spiral ganglion neurons (SGNs) and hair cells in the cochlea using 3xTg-AD mouse model of AD and R6/2-HD mouse model of HD. We found that the threshold of ABR, but not DPOAE, was significantly increased in AD mice from 9 months of age and thereafter. The significant loss of SGNs, but not hair cells, was observed in the cochlea of 9- and 12-month AD mice. On the other hand, we found that both ABR and DPOAE thresholds were significantly increased in HD mice from 2 months of age and thereafter. The large loss of hair cells and the small loss of SGNs were observed in the cochlea of 3-month HD mice. Furthermore, the prestin expression in outer hair cells (OHCs) was significantly decreased in HD mice from 2 months of age and thereafter, and the loss of prestin expression was earlier before OHCs death in HD mice. Different from HD mice, the prestin expression in OHCs in AD mice was not changed even at 12 months of age. Our data suggest that cochlear pathology contributing to hearing loss is quite different between transgenic mice of AD and HD. More detailed pathological mechanisms for hearing loss between AD and HD need further study. PMID:26717914

  3. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

    OpenAIRE

    Han-yu Dong; Xin-mei Jiang; Chun-bo Niu; Lin Du; Jun-yan Feng; Fei-yong Jia

    2016-01-01

    To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve...

  4. 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...

  5. 7, 8-dihydroxycoumarin improves neurological function in a mouse model of sciatic nerve injury☆

    OpenAIRE

    Du, Jianshi; Zhao, Qing; ZHANG, YINGLI; Wang, Yu; Ma, Ming

    2012-01-01

    In the present study, a mouse model of sciatic nerve injury was treated with intraperitoneal injection of 7, 8-dihydroxycoumarin (10, 5, or 2.5 mg/kg per day). Western blot and real-time PCR results showed that growth associated protein 43 expression was significantly increased in the L4-6 segments of the spinal cord. The amplitude and velocity of motor nerve conduction in the sciatic nerve were significantly increased in model mice. In addition, the appearance of the myelin sheath in the inj...

  6. Unaltered lactate and glucose transporter levels in the MPTP mouse model of Parkinson's disease

    DEFF Research Database (Denmark)

    Puchades, Maja; Sogn, Carl Johan; Maehlen, Jan;

    2013-01-01

    levels of the transporters for monocarboxylates (MCT1 and MCT2) and glucose (GLUT1) in the MPTP mouse model of PD. RESULTS: We found that MCT1 and GLUT1 were densely located in blood vessel endothelium, while MCT2 was present in perivascular astrocytic end feet processes in the substantia nigra...... and the striatum of control mice. We found that the localisation and densities of MCTs and GLUT1 were unaltered in the PD model. DISCUSSION: This is the first study reporting on the distribution of metabolic transporters in PD. Our results suggest that, although there are metabolic impairments in PD, the levels...

  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. OB glue paste technique for establishing nude mouse human gastric cancer orthotopic transplantation models

    Institute of Scientific and Technical Information of China (English)

    Jun Shi; Guo-Jing Zheng; Xiao-Mei Su; Ya-Lin Chen; Yan-Fang Liu; Ling Xu; Pin-Kang Wei; Shen Zhang; Zhi-Feng Qin; Jun Li; Da-Zhi Sun; Yan Xiao; Zhi-Hong Yu; Hui-Ming Lin

    2008-01-01

    AIM: To establish nude mouse human gastric cancer orthotopic transplantation models using OB glue paste technique.METHODS: Using OB glue paste technique,orthtopic transplantation models were established by implanting SGC-7901 and MKN-45 human gastric cancer cell strains into the gastric wall of nude mice.Biological features,growth of the implanted tumors,the success rate of transplantation and the rate of auto-metastasis of the two models were observed.RESULTS: The success rates of orthotopic transplantation of the two models were 94.20% and 96%.The rates of hepatic metastasis,pulmonary metastasis,peritoneal metastasis,lymphocytic metastasis and splenic metastasis were 42.13% and 94.20%,48.43% and 57.97%,30.83% and 36.96%,67.30% and 84.06%,and 59.75% and 10.53%,respectively.The occurrence of ascites was 47.80% and 36.96%.CONCLUSION: OB glue paste technique is easy to follow.The biological behaviors of the nude mouse human gastric cancer orthotopic transplantation models established with this technique are similar to the natural processes of growth and metastasis of human gastric cancer,and,therefore,can be used as an ideal model for experimental research of proliferative metastasis of tumors.

  9. The impact of mouse passaging of Mycobacterium tuberculosis strains prior to virulence testing in the mouse and guinea pig aerosol models.

    Directory of Open Access Journals (Sweden)

    Paul J Converse

    Full Text Available BACKGROUND: It has been hypothesized that the virulence of lab-passaged Mycobacterium tuberculosis and recombinant M. tuberculosis mutants might be reduced due to multiple in vitro passages, and that virulence might be augmented by passage of these strains through mice before quantitative virulence testing in the mouse or guinea pig aerosol models. METHODOLOGY/PRINCIPAL FINDINGS: By testing three M. tuberculosis H37Rv samples, one deletion mutant, and one recent clinical isolate for survival by the quantitative organ CFU counting method in mouse or guinea pig aerosol or intravenous infection models, we could discern no increase in bacterial fitness as a result of passaging of M. tuberculosis strains in mice prior to quantitative virulence testing in two animal models. Surface lipid expression as assessed by neutral red staining and thin-layer chromatography for PDIM analysis also failed to identify virulence correlates. CONCLUSIONS/SIGNIFICANCE: These results indicate that animal passaging of M. tuberculosis strains prior to quantitative virulence testing in mouse or guinea pig models does not enhance or restore potency to strains that may have lost virulence due to in vitro passaging. It is critical to verify virulence of parental strains before genetic manipulations are undertaken and comparisons are made.

  10. Mouse Models of Hereditary Haemorrhagic Telangiectasia: Recent Advances and Future Challenges

    Directory of Open Access Journals (Sweden)

    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

  11. Complementarity of ultrasound and fluorescence imaging in an orthotopic mouse model of pancreatic cancer

    International Nuclear Information System (INIS)

    Pancreatic cancer is a devastating disease characterized by dismal 5-year survival rates and limited treatment options. In an effort to provide useful models for preclinical evaluation of new experimental therapeutics, we and others have developed orthotopic mouse models of pancreatic cancer. The utility of these models for pre-clinical testing is dependent upon quantitative, noninvasive methods for monitoring in vivo tumor progression in real time. Toward this goal, we performed whole-body fluorescence imaging and ultrasound imaging to evaluate and to compare these noninvasive imaging modalities for assessing tumor burden and tumor progression in an orthotopic mouse model of pancreatic cancer. The human pancreatic cancer cell line XPA-1, engineered for stable, high-level expression of red fluorescent protein (RFP), was implanted into the pancreas of nude mice using orthotopic implantation. The tumors were allowed to grow over a period of one to several weeks during which time the mice were imaged using both fluorescence imaging and ultrasound imaging to measure tumor burden and to monitor tumor growth. Whole-body fluorescence imaging and ultrasound imaging both allowed for the visualization and measurement of orthotopic pancreatic tumor implants in vivo. The imaging sessions were well-tolerated by the mice and yielded data which correlated well in the quantitative assessment of tumor burden. Whole-body fluorescence and two-dimensional ultrasound imaging showed a strong correlation for measurement of tumor size over a range of tumor sizes (R2 = 0.6627, P = 0.003 for an exposure time of 67 msec and R2 = 0.6553, P = 0.003 for an exposure time of 120 msec). Our findings suggest a complementary role for fluorescence imaging and ultrasound imaging in assessing tumor burden and tumor progression in orthotopic mouse models of human cancer

  12. 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.

  13. Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis.

    Science.gov (United States)

    Mor, Visesato; Farnoud, Amir M; Singh, Ashutosh; Rella, Antonella; Tanno, Hiromasa; Ishii, Keiko; Kawakami, Kazuyoshi; Sato, Toshiya; Del Poeta, Maurizio

    2016-01-01

    Cryptococcus neoformans is an opportunistic fungal pathogen and the causative agent of the disease cryptococcosis. Cryptococcosis is initiated as a pulmonary infection and in conditions of immune deficiency disseminates to the blood stream and central nervous system, resulting in life-threatening meningoencephalitis. A number of studies have focused on the development of a vaccine against Cryptococcus, primarily utilizing protein-conjugated components of the Cryptococcus polysaccharide capsule as antigen. However, there is currently no vaccine against Cryptococcus in the clinic. Previous studies have shown that the glycosphingolipid, glucosylceramide (GlcCer), is a virulence factor in C. neoformans and antibodies against this lipid inhibit fungal growth and cell division. In the present study, we have investigated the possibility of using GlcCer as a therapeutic agent against C. neoformans infections in mouse models of cryptococcosis. GlcCer purified from a non-pathogenic fungus, Candida utilis, was administered intraperitoneally, prior to infecting mice with a lethal dose of C. neoformans. GlcCer administration prevented the dissemination of C. neoformans from the lungs to the brain and led to 60% mouse survival. GlcCer administration did not cause hepatic injury and elicited an anti-GlcCer antibody response, which was observed independent of the route of administration and the strains of mouse. Taken together, our results suggest that fungal GlcCer can protect mice against lethal doses of C. neoformans infection and can provide a viable vaccination strategy against Cryptococcus. PMID:27082428

  14. Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3.

    Science.gov (United States)

    Boy, Jana; Schmidt, Thorsten; Wolburg, Hartwig; Mack, Andreas; Nuber, Silke; Böttcher, Martin; Schmitt, Ina; Holzmann, Carsten; Zimmermann, Frank; Servadio, Antonio; Riess, Olaf

    2009-11-15

    Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a CAG repeat tract that affects the MJD1 gene which encodes the ataxin-3 protein. In order to analyze whether symptoms caused by ataxin-3 with an expanded repeat are reversible in vivo, we generated a conditional mouse model of SCA3 using the Tet-Off system. We used a full-length human ataxin-3 cDNA with 77 repeats in order to generate the responder mouse line. After crossbreeding with a PrP promoter mouse line, double transgenic mice developed a progressive neurological phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired Rotarod performance and lower body weight gain. When ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. These results show that reducing the production of pathogenic ataxin-3 indeed may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time. PMID:19666958

  15. A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema.

    Science.gov (United States)

    Victorio, Carla Bianca Luena; Xu, Yishi; Ng, Qimei; Chua, Beng Hooi; Alonso, Sylvie; Chow, Vincent T K; Chua, Kaw Bing

    2016-01-01

    Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)-the main cause of EV-A71 infection-related mortality-is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications. PMID:27357918

  16. Computational multiscale toxicodynamic modeling of silver and carbon nanoparticle effects on mouse lung function.

    Directory of Open Access Journals (Sweden)

    Dwaipayan Mukherjee

    Full Text Available A computational, multiscale toxicodynamic model has been developed to quantify and predict pulmonary effects due to uptake of engineered nanomaterials (ENMs in mice. The model consists of a collection of coupled toxicodynamic modules, that were independently developed and tested using information obtained from the literature. The modules were developed to describe the dynamics of tissue with explicit focus on the cells and the surfactant chemicals that regulate the process of breathing, as well as the response of the pulmonary system to xenobiotics. Alveolar type I and type II cells, and alveolar macrophages were included in the model, along with surfactant phospholipids and surfactant proteins, to account for processes occurring at multiple biological scales, coupling cellular and surfactant dynamics affected by nanoparticle exposure, and linking the effects to tissue-level lung function changes. Nanoparticle properties such as size, surface chemistry, and zeta potential were explicitly considered in modeling the interactions of these particles with biological media. The model predictions were compared with in vivo lung function response measurements in mice and analysis of mice lung lavage fluid following exposures to silver and carbon nanoparticles. The predictions were found to follow the trends of observed changes in mouse surfactant composition over 7 days post dosing, and are in good agreement with the observed changes in mouse lung function over the same period of time.

  17. Combination of mouse models and genomewide association studies highlights novel genes associated with human kidney function.

    Science.gov (United States)

    Jing, Jiaojiao; Pattaro, Cristian; Hoppmann, Anselm; Okada, Yukinori; Fox, Caroline S; Köttgen, Anna

    2016-10-01

    Genomewide association studies have identified numerous chronic kidney disease-associated genetic variants, but often do not pinpoint causal genes. This limitation was addressed by combining Mouse Genome Informatics with human genomewide association studies of kidney function. Genes for which mouse models showed abnormal renal physiology, morphology, glomerular filtration rate (GFR), or urinary albumin-to-creatinine ratio were identified from Mouse Genome Informatics. The corresponding human orthologs were then evaluated for GFR-associated single-nucleotide polymorphisms in 133,814 individuals and urinary albumin-to-creatinine ratio-associated SNPs in 54,451 individuals in genome-wide association studies meta-analysis of the CKDGen Consortium. After multiple testing corrections, significant associations with estimated GFR in humans were identified for single-nucleotide polymorphisms in 2, 7, and 17 genes causing abnormal GFR, abnormal physiology, and abnormal morphology in mice, respectively. Genes identified for abnormal kidney morphology showed significant enrichment for estimated GFR-associated single-nucleotide polymorphisms. In total, 19 genes contained variants associated with estimated GFR or the urinary albumin-to-creatinine ratio of which 16 mapped into previously reported genomewide significant loci. CYP26A1 and BMP4 emerged as novel signals subsequently validated in a large, independent study. An additional gene, CYP24A1, was discovered after conditioning on a published nearby association signal. Thus, our novel approach to combine comprehensive mouse phenotype information with human genomewide association studies data resulted in the identification of candidate genes for kidney disease pathogenesis. PMID:27263491

  18. A two-compartment model of VEGF distribution in the mouse.

    Directory of Open Access Journals (Sweden)

    Phillip Yen

    Full Text Available Vascular endothelial growth factor (VEGF is a key regulator of angiogenesis--the growth of new microvessels from existing microvasculature. Angiogenesis is a complex process involving numerous molecular species, and to better understand it, a systems biology approach is necessary. In vivo preclinical experiments in the area of angiogenesis are typically performed in mouse models; this includes drug development targeting VEGF. Thus, to quantitatively interpret such experimental results, a computational model of VEGF distribution in the mouse can be beneficial. In this paper, we present an in silico model of VEGF distribution in mice, determine model parameters from existing experimental data, conduct sensitivity analysis, and test the validity of the model. The multiscale model is comprised of two compartments: blood and tissue. The model accounts for interactions between two major VEGF isoforms (VEGF(120 and VEGF(164 and their endothelial cell receptors VEGFR-1, VEGFR-2, and co-receptor neuropilin-1. Neuropilin-1 is also expressed on the surface of parenchymal cells. The model includes transcapillary macromolecular permeability, lymphatic transport, and macromolecular plasma clearance. Simulations predict that the concentration of unbound VEGF in the tissue is approximately 50-fold greater than in the blood. These concentrations are highly dependent on the VEGF secretion rate. Parameter estimation was performed to fit the simulation results to available experimental data, and permitted the estimation of VEGF secretion rate in healthy tissue, which is difficult to measure experimentally. The model can provide quantitative interpretation of preclinical animal data and may be used in conjunction with experimental studies in the development of pro- and anti-angiogenic agents. The model approximates the normal tissue as skeletal muscle and includes endothelial cells to represent the vasculature. As the VEGF system becomes better characterized in

  19. Current humanized mouse models for studying human immunology and HIV-1 immuno-pathogenesis

    Institute of Scientific and Technical Information of China (English)

    MEISSNER; Eric

    2010-01-01

    A robust animal model for "hypothesis-testing/mechanistic" research in human immunology and immuno-pathology should meet the following criteria.First,it has well-studied hemato-lymphoid organs and target cells similar to those of humans.Second,the human pathogens establish infection and lead to relevant diseases.Third,it is genetically inbred and can be manipulated via genetic,immunological and pharmacological means.Many human-tropic pathogens such as HIV-1 fail to infect murine cells due to the blocks at multiple steps of their life cycle.The mouse with a reconstituted human immune system and other human target organs is a good candidate.A number of human-mouse chimeric models with human immune cells have been developed in the past 20 years,but most with only limited success due to the selective engraftment of xeno-reactive human T cells in hu-PBL-SCID mice or the lack of significant human immune responses in the SCID-hu Thy/Liv mouse.This review summarizes the current understanding of HIV-1 immuno-pathogenesis in human patients and in SIV-infected primate models.It also reviews the recent progress in the development of humanized mouse models with a functional human immune system,especially the recent progress in the immunodeficient mice that carry a defective gammaC gene.NOD/SCID/gammaC-/(NOG or NSG) or the Rag2-/-/gammaC-/double knockout (DKO) mice,which lack NK as well as T and B cells (NTB-null mice),have been used to reconstitute a functional human immune system in central and peripheral lymphoid organs with human CD34+ HSC.These NTB-hu HSC humanized models have been used to investigate HIV-1 infection,immuno-pathogenesis and therapeutic interventions.Such models,with further improvements,will contribute to study human immunology,human-tropic pathogens as well as human stem cell biology in the tissue development and function in vivo.

  20. 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.

  1. Toluene diisocyanate and methylene diphenyl diisocyanate: asthmatic response and cross-reactivity in a mouse model.

    Science.gov (United States)

    Pollaris, Lore; Devos, Fien; De Vooght, Vanessa; Seys, Sven; Nemery, Benoit; Hoet, Peter H M; Vanoirbeek, Jeroen A J

    2016-07-01

    Both 2,4-toluene diisocyanate (TDI) and 4,4-methylene diphenyl diisocyanate (MDI) can cause occupational asthma. In this study, we optimized our mouse model of chemical-induced asthma in the C57Bl/6 mice strain using the model agent TDI. Furthermore, we validated MDI in this mouse model and investigated whether cross-reactivity between TDI and MDI is present. On days 1 and 8, C57Bl/6 mice were dermally treated (20 µl/ear) with 3 % MDI, 2 % TDI or the vehicle acetone olive oil (AOO) (3:2). On day 15, they received a single oropharyngeal challenge with 0.04 % MDI, 0.01 % TDI or the vehicle AOO (4:1). One day later, airway hyperreactivity (AHR) and pulmonary inflammation in the bronchoalveolar lavage (BAL) were assessed. Furthermore, total serum IgE levels, lymphocyte subpopulations in auricular lymph nodes and cytokine levels in supernatants of lymphocytes were measured. Both dermal sensitization with TDI or MDI resulted in increased total serum IgE levels along with T and B cell proliferation in the auricular lymph nodes. The auricular lymphocytes showed an increased release of both Th2 and Th1 cytokines. Mice sensitized and challenged with either TDI or MDI showed AHR, along with a predominant neutrophil lung inflammation. Mice sensitized with MDI and challenged with TDI or the other way around showed no AHR, nor BAL inflammation. Both TDI and MDI are able to induce an asthma-like response in this mouse model. However, cross-reactivity between both diisocyanates remained absent. PMID:26468151

  2. 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.

  3. PD-1 Blockage Reverses Immune Dysfunction and Hepatitis B Viral Persistence in a Mouse Animal Model

    Science.gov (United States)

    Tzeng, Horng-Tay; Tsai, Hwei-Fang; Liao, Hsiu-Jung; Lin, Yi-Jiun; Chen, Lieping; Chen, Pei-Jer; Hsu, Ping-Ning

    2012-01-01

    Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Recent studies in animal models of viral infection indicate that the interaction between the inhibitory receptor, programmed death (PD)-1, on lymphocytes and its ligand (PD-L1) play a critical role in T-cell exhaustion by inducing T-cell inactivation. High PD-1 expression levels by peripheral T-lymphocytes and the possibility of improving T-cell function by blocking PD-1-mediated signaling confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1 and PD-L1 blockade on intrahepatic infiltrating T-cells in our recently developed mouse model of HBV persistence. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1-expressing CD8+ and CD4+ T cells in mice with HBV persistence, but PD-1 upregulation was resolved in mice which had cleared HBV. The Intrahepatic CD8+ T-cells expressed higher levels of PD-1 and lower levels of CD127 in mice with HBV persistence. Blockade of PD-1/PD-L1 interactions increased HBcAg-specific interferon (IFN)-γ production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with PD-L1 by an anti-PD-1 monoclonal antibody (mAb) reversed the exhausted phenotype in intrahepatic T lymphocytes and viral persistence to clearance of HBV in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence of HBV infection in a mouse animal model, suggesting that the anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection. PMID:22761734

  4. PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model.

    Directory of Open Access Journals (Sweden)

    Horng-Tay Tzeng

    Full Text Available Persistent hepatitis B viral (HBV infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC. Recent studies in animal models of viral infection indicate that the interaction between the inhibitory receptor, programmed death (PD-1, on lymphocytes and its ligand (PD-L1 play a critical role in T-cell exhaustion by inducing T-cell inactivation. High PD-1 expression levels by peripheral T-lymphocytes and the possibility of improving T-cell function by blocking PD-1-mediated signaling confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1 and PD-L1 blockade on intrahepatic infiltrating T-cells in our recently developed mouse model of HBV persistence. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1-expressing CD8+ and CD4+ T cells in mice with HBV persistence, but PD-1 upregulation was resolved in mice which had cleared HBV. The Intrahepatic CD8+ T-cells expressed higher levels of PD-1 and lower levels of CD127 in mice with HBV persistence. Blockade of PD-1/PD-L1 interactions increased HBcAg-specific interferon (IFN-γ production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with PD-L1 by an anti-PD-1 monoclonal antibody (mAb reversed the exhausted phenotype in intrahepatic T lymphocytes and viral persistence to clearance of HBV in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence of HBV infection in a mouse animal model, suggesting that the anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.

  5. 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.

  6. Assessment of photoacoustic computed tomography to classify tissue in a polycystic-kidney disease mouse model

    Science.gov (United States)

    Liu, Bo; Gattone, Vincent H., II; Kruger, Robert A.; Stantz, Keith M.

    2006-02-01

    Purpose: The purpose of this study is to evaluate PCT Imaging technique to classify tissue and extract kidney cysts in pcy mice model of human adolescent nephronophthisis. Method: Four mice with late stages of nephronophthisis with polycystic kidney disease-PKD and one normal mouse were scanned in the PCT Small Animal Scanner. Both vivo and ex-vivo images of mice kidney were taken at wavelength from 680 nm to 940 nm. The ex-vivo PCT images were compared with histology photographs to check the sensitivity of detecting cysts. Histograms of kidney images were generated over slices and fitted to Gaussian-curve model for volumetric analysis. The portions of cysts in kidneys were estimated and kidney images were segmented by three different colors to present the distribution of different tissues. Result: A good correspondence between PCT imaging findings and PKD histology result was observed. Histogram curves from images of pcy kidneys and normal kidneys were fitted to Gaussian-curve model. Portions of cysts, parenchyma and area of high level hemoglobin were estimated according to the curve fit result. A growth of cysts associated with relatively volume decrease of parenchyma and tissues with high perfusion of hemoglobin was observed. Conclusion: The PCT enabled visualization of renal cysts for mouse model and had the potential for volumetric measurements of kidney.

  7. The reemergence of long-term potentiation in aged Alzheimer’s disease mouse model

    Science.gov (United States)

    Huh, Seonghoo; Baek, Soo-Ji; Lee, Kyung-Hwa; Whitcomb, Daniel J.; Jo, Jihoon; Choi, Seong-Min; Kim, Dong Hyun; Park, Man-Seok; Lee, Kun Ho; Kim, Byeong C.

    2016-01-01

    Mouse models of Alzheimer’s disease (AD) have been developed to study the pathophysiology of amyloid β protein (Aβ) toxicity, which is thought to cause severe clinical symptoms such as memory impairment in AD patients. However, inconsistencies exist between studies using these animal models, specifically in terms of the effects on synaptic plasticity, a major cellular model of learning and memory. Whereas some studies find impairments in plasticity in these models, others do not. We show that long-term potentiation (LTP), in the CA1 region of hippocampal slices from this mouse, is impared at Tg2576 adult 6–7 months old. However, LTP is inducible again in slices taken from Tg2576 aged 14–19 months old. In the aged Tg2576, we found that the percentage of parvalbumin (PV)-expressing interneurons in hippocampal CA1-3 region is significantly decreased, and LTP inhibition or reversal mediated by NRG1/ErbB signaling, which requires ErbB4 receptors in PV interneurons, is impaired. Inhibition of ErbB receptor kinase in adult Tg2576 restores LTP but impairs depotentiation as shown in aged Tg2576. Our study suggests that hippocampal LTP reemerges in aged Tg2576. However, this reemerged LTP is an insuppressible form due to impaired NRG1/ErbB signaling, possibly through the loss of PV interneurons. PMID:27377368

  8. Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Tesla, Rachel; Wolf, Hamilton Parker; Xu, Pin; Drawbridge, Jordan; Estill, Sandi Jo; Huntington, Paula; McDaniel, Latisha; Knobbe, Whitney; Burket, Aaron; Tran, Stephanie; Starwalt, Ruth; Morlock, Lorraine; Naidoo, Jacinth; Williams, Noelle S; Ready, Joseph M; McKnight, Steven L; Pieper, Andrew A

    2012-10-16

    We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS.

  9. Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

    Directory of Open Access Journals (Sweden)

    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.

  10. Development and degeneration of cone bipolar cells are independent of cone photoreceptors in a mouse model of retinitis pigmentosa

    OpenAIRE

    Miao Chen; Ke Wang; Bin Lin

    2012-01-01

    Retinal photoreceptors die during retinal synaptogenesis in a portion of retinal degeneration. Whether cone bipolar cells establish regular retinal mosaics and mature morphologies, and resist degeneration are not completely understood. To explore these issues, we backcrossed a transgenic mouse expressing enhanced green fluorescent protein (EGFP) in one subset of cone bipolar cells (type 7) into rd1 mice, a classic mouse model of retinal degeneration, to examine the development and survival of...

  11. Differential Hippocampal Gene Expression and Pathway Analysis in an Etiology-Based Mouse Model of Major Depressive Disorder

    OpenAIRE

    Zubenko, George S.; Hughes, Hugh B.; Jordan, Rick M.; Lyons-Weiler, James; Cohen, Bruce M.

    2014-01-01

    We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence witha6-base DNA sequence from the human CREB1promoterthat is associated with MDD in individuals from families with recurrent, early-onset MDD (RE-MDD). In the current study, we explored the effect of the pathogenic Creb1 allele on ...

  12. Developing a Nanoparticle-Delivered High-Efficacy Treatment for Infantile Hemangiomas Using a Mouse Hemangioendothelioma Model.

    OpenAIRE

    Orbay, H; Li, Y; Xiao, W; Cherry, SR; Lam, K; Sahar, DE

    2016-01-01

    Current treatments for infantile hemangiomas have unpredictable outcomes. The authors' aim was to develop a nanoporphyrin-delivered, high-efficacy treatment for infantile hemangiomas using a mouse hemangioendothelioma model.The authors injected mouse hemangioendothelioma cells intradermally to axillary regions of 5-week-old, female, nude mice (n = 19) to induce hemangioendothelioma growth. They documented nanoporphyrin accumulation in hemangioendotheliomas using positron emission tomography. ...

  13. The transcobalamin receptor knockout mouse: a model for vitamin B12 deficiency in the central nervous system

    OpenAIRE

    Lai, Shao-Chiang; Nakayama, Yasumi; Sequeira, Jeffrey M.; Wlodarczyk, Bogdan J.; Cabrera, Robert M.; Finnell, Richard H.; Bottiglieri, Teodoro; Quadros, Edward V.

    2013-01-01

    The membrane receptor (TCblR/CD320) for transcobalamin (TC)-bound cobalamin (Cbl) facilitates the cellular uptake of Cbl. A genetically modified mouse model involving ablation of the CD320 gene was generated to study the effects on cobalamin homeostasis. The nonlethal nature of this knockout and the lack of systemic cobalamin deficiency point to other mechanisms for cellular Cbl uptake in the mouse. However, severe cobalamin depletion in the central nervous system (CNS) after birth (P

  14. Roles of Macrophages and Neutrophils in the Early Host Response to Bacillus anthracis Spores in a Mouse Model of Infection

    OpenAIRE

    Cote, Christopher K.; Van Rooijen, Nico; Welkos, Susan L.

    2006-01-01

    The development of new approaches to combat anthrax requires that the pathogenesis and host response to Bacillus anthracis spores be better understood. We investigated the roles that macrophages and neutrophils play in the progression of infection by B. anthracis in a mouse model. Mice were treated with a macrophage depletion agent (liposome-encapsulated clodronate) or with a neutrophil depletion agent (cyclophosphamide or the rat anti-mouse granulocyte monoclonal antibody RB6-8C5), and the a...

  15. A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype

    OpenAIRE

    Syder, Andrew J.; Karam, Sherif M.; Mills, Jason C.; Ippolito, Joseph E.; Ansari, Habib R.; Farook, Vidya; Jeffrey I Gordon

    2004-01-01

    Human neuroendocrine cancers (NECs) arise in various endoderm-derived epithelia, have diverse morphologic features, exhibit a wide range of growth phenotypes, and generally have obscure cellular origins and ill-defined molecular mediators of initiation and progression. We describe a transgenic mouse model of metastatic gastric cancer initiated by expressing simian virus 40 large tumor antigen (SV40 TAg), under control of regulatory elements from the mouse Atp4b gene, in the progenitors of aci...

  16. Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome

    Science.gov (United States)

    Nilsson, Simon RO.; Fejgin, Kim; Gastambide, Francois; Vogt, Miriam A.; Kent, Brianne A.; Nielsen, Vibeke; Nielsen, Jacob; Gass, Peter; Robbins, Trevor W.; Saksida, Lisa M.; Stensbøl, Tine B.; Tricklebank, Mark D.; Didriksen, Michael; Bussey, Timothy J.

    2016-01-01

    A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus – within the current protocols – the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional “hits” being required for phenotypic expression. PMID:27507786

  17. 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.

  18. PKC Theta Ablation Improves Healing in a Mouse Model of Muscular Dystrophy

    Science.gov (United States)

    Madaro, Luca; Pelle, Andrea; Nicoletti, Carmine; Crupi, Annunziata; Marrocco, Valeria; Bossi, Gianluca; Soddu, Silvia; Bouché, Marina

    2012-01-01

    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. PMID:22348094

  19. Myricetin Prevents Alveolar Bone Loss in an Experimental Ovariectomized Mouse Model of Periodontitis.

    Science.gov (United States)

    Huang, Jialiang; Wu, Chuanlong; Tian, Bo; Zhou, Xiao; Ma, Nian; Qian, Yufen

    2016-03-22

    Periodontitis is a common chronic inflammatory disease, which leads to alveolar bone resorption. Healthy and functional alveolar bone, which can support the teeth and enable their movement, is very important for orthodontic treatment. Myricetin inhibited osteoclastogenesis by suppressing the expression of some genes, signaling pathways, and cytokines. This study aimed to investigate the effects of myricetin on alveolar bone loss in an ovariectomized (OVX) mouse model of periodontitis as well as in vitro osteoclast formation and bone resorption. Twenty-four healthy eight-week-old C57BL/J6 female mice were assigned randomly to four groups: phosphate-buffered saline (PBS) control (sham) OVX + ligature + PBS (vehicle), and OVX + ligature + low or high (2 or 5 mg∙kg(-1)∙day(-1), respectively) doses of myricetin. Myricetin or PBS was injected intraperitoneally (i.p.) every other day for 30 days. The maxillae were collected and subjected to further examination, including micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining; a resorption pit assay was also performed in vitro to evaluate the effects of myricetin on receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis. Myricetin, at both high and low doses, prevented alveolar bone resorption and increased alveolar crest height in the mouse model and inhibited osteoclast formation and bone resorption in vitro. However, myricetin was more effective at high dose than at low dose. Our study demonstrated that myricetin had a positive effect on alveolar bone resorption in an OVX mouse model of periodontitis and, therefore, may be a potential agent for the treatment of periodontitis and osteoporosis.

  20. A novel transgenic mouse model of Chinese Charcot-Marie-Tooth disease type 2L

    Institute of Scientific and Technical Information of China (English)

    Ruxu Zhang; Qian Pan; Beisha Tang; Fufeng Zhang; Xiaobo Li; Shunxiang Huang; Xiaohong Zi; Ting Liu; Sanmei Liu; Xuning Li; Kun Xia

    2014-01-01

    We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was respon-sible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141NHSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis conifrmed integra-tion of the K141NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141NHSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assess-ment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was signiifcantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated ifber density, notable axonal edema and vacuolar degeneration in K141NHSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These ifndings indicate that the K141NHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.

  1. Enzyme replacement therapy of a novel humanized mouse model of globoid cell leukodystrophy.

    Science.gov (United States)

    Matthes, Frank; Andersson, Claes; Stein, Axel; Eistrup, Carl; Fogh, Jens; Gieselmann, Volkmar; Wenger, David A; Matzner, Ulrich

    2015-09-01

    An inherited deficiency of β-galactosylceramidase (GALC) causes the lysosomal storage disease globoid cell leukodystrophy (GLD). The disease is characterized by the accumulation of the cytotoxic metabolite psychosine (galactosylsphingosine), causing rapid degeneration of myelinating cells. Most patients suffer from the infantile form of GLD with onset of disease between 3 and 6 months after birth and death by 2 years of age. The most widely used animal model of GLD, the twitcher mouse, presents with an even more rapid course of disease and death around 40 days of age. We have generated a novel "humanized" mouse model of GLD by inserting a human GALC cDNA containing an adult-onset patient mutation into the murine GALC gene. Humanized GALC mice exhibit pathological hallmarks of GLD including psychosine accumulation, neuroinflammation, CNS infiltration of macrophages, astrogliosis and demyelination. Residual GALC activities in mouse tissues are low and the mice display a median lifespan of 46 days. Due to the expression of the human transgene, the mice do not develop an immune response against rhGALC, rendering the animal model suitable for therapies based on human enzyme. Intravenously injected rhGALC was able to surmount the blood-brain barrier and was targeted to lysosomes of brain macrophages, astrocytes and neurons. High-dose enzyme replacement therapy started at postnatal day 21 reduced the elevated psychosine levels in the peripheral and central nervous system by 14-16%, but did not ameliorate neuroinflammation, demyelination and lifespan. These results may indicate that treatment must be started earlier before pathology occurs. PMID:25956830

  2. Huntington's disease mouse models online: high-resolution MRI images with stereotaxic templates for computational neuroanatomy.

    Directory of Open Access Journals (Sweden)

    Stephen J Sawiak

    Full Text Available Magnetic resonance imaging (MRI has proved to be an ideal modality for non-destructive and highly detailed assessment of structural morphology in biological tissues. Here we used MRI to make a dataset of ex vivo brains from two different rodent models of Huntington's disease (HD, the R6/2 line and the YAC 128 mouse. We are making the whole dataset (399 transgenic HD and wildtype (WT brains, from mice aged 9-80 weeks publicly available. These data will be useful, not only to investigators interested in the study of HD, but also to researchers of computational neuroanatomy who may not have access to such large datasets from mouse models. Here we demonstrate a number of uses of such data, for example to produce maps of grey and white matter and cortical thickness. As an example of how the library might provide insights in mouse models of HD, we calculated whole brain grey matter volumes across different age groups with different numbers of cytosine-adenine-guanine (CAG repeats in a fragment of the gene responsible for HD in humans. (The R6/2 dataset was obtained from an allelic series of R6/2 mice carrying a range of CAG repeat lengths between 109 and 464. This analysis revealed different trajectories for each fragment length. In particular there was a gradient of decreasing pathology with longer CAG repeat lengths, reflecting our previous findings with behavioural and histological studies. There will be no constraints placed on the use of the datasets included here. The original data will be easily and permanently accessible via the University of Cambridge data repository (http://www.dspace.cam.ac.uk/handle/1810/243361.

  3. Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

    Directory of Open Access Journals (Sweden)

    Sara Anjomani Virmouni

    Full Text Available Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats, YG8R (90 and 190 GAA repeats and YG22R (190 GAA repeats.We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R.Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.

  4. A novel GAA-repeat-expansion-based mouse model of Friedreich’s ataxia

    Directory of Open Access Journals (Sweden)

    Sara Anjomani Virmouni

    2015-03-01

    Full Text Available Friedreich’s ataxia (FRDA is an autosomal recessive neurodegenerative disorder caused by a GAA repeat expansion mutation within intron 1 of the FXN gene, resulting in reduced levels of frataxin protein. We have previously reported the generation of human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing 90–190 GAA repeats, but the presence of multiple GAA repeats within these mice is considered suboptimal. We now describe the cellular, molecular and behavioural characterisation of a newly developed YAC transgenic FRDA mouse model, designated YG8sR, which we have shown by DNA sequencing to contain a single pure GAA repeat expansion. The founder YG8sR mouse contained 120 GAA repeats but, due to intergenerational expansion, we have now established a colony of YG8sR mice that contain ~200 GAA repeats. We show that YG8sR mice have a single copy of the FXN transgene, which is integrated at a single site as confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We have identified significant behavioural deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8sR FRDA mice compared with control Y47R and wild-type (WT mice. We have also detected increased somatic GAA repeat instability in the brain and cerebellum of YG8sR mice, together with significantly reduced expression of FXN, FAST-1 and frataxin, and reduced aconitase activity, compared with Y47R mice. Furthermore, we have confirmed the presence of pathological vacuoles within neurons of the dorsal root ganglia (DRG of YG8sR mice. These novel GAA-repeat-expansion-based YAC transgenic FRDA mice, which exhibit progressive FRDA-like pathology, represent an excellent model for the investigation of FRDA disease mechanisms and therapy.

  5. Proteome and Transcriptome Profiles of a Her2/Neu-driven Mouse Model of Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Schoenherr, Regine M.; Kelly-Spratt, Karen S.; Lin, Chen Wei; Whiteaker, Jeffrey R.; Liu, Tao; Holzman, Ted; Coleman, Ilsa; Feng, Li-Chia; Lorentzen, Travis D.; Krasnoselsky, Alexei L.; Wang, Pei; Liu, Yan; Gurley, Kay E.; Amon, Lynn M.; Schepmoes, Athena A.; Moore, Ronald J.; Camp, David G.; Chodosh, Lewis A.; Smith, Richard D.; Nelson, Peter S.; McIntosh, Martin; Kemp, Christopher; Paulovich, Amanda G.

    2011-04-01

    In recent years, mouse models have proven to be invaluable in expanding our understanding of cancer biology. We have amassed a tremendous amount of proteomics and transcriptomics data profiling blood and tissues from a Her2-driven mouse model of breast cancer that closely recapitulates the pathology and natural history of human breast cancer. The purpose of this report is to make all of these data publicly available in raw and processed forms, as a resource to the community. Importantly, high quality biospecimens from this same mouse model are freely available through a sample repository that we established, so researchers can readily obtain samples to test biological hypotheses without the need of breeding animals and collecting biospecimens. Specifically, six proteomics and six transcriptomics datasets are available, with the former encompassing 841 liquid chromatography-tandem mass spectrometry (LC-MS/MS) experiments of both plasma and tissue samples, and the latter including 255 individual microarray analyses of five different tissue types (thymus, spleen, liver, blood cells, and breast ± laser capture microdissection). A total of 18,880 unique peptides were identified with a PeptideProphet error rate ≤1%, with 3884 non-redundant protein groups identified in five plasma datasets, and 1659 non-redundant protein groups in a tissue dataset (4977 non-redundant protein groups in total). We anticipate that these data will be of use to the community for software tool development, investigations of analytical variation in MS/MS data, development of quality control tools (multiple technical replicates are provided for a subset of the data), empirical selection of proteotypic peptides for multiple reaction monitoring mass spectrometry, and for advancing our understanding of cancer biology.

  6. Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three-Dimensional Ultrasound Imaging Technique

    Directory of Open Access Journals (Sweden)

    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.

  7. Novel object exploration in the C58/J mouse model of autistic-like behavior.

    Science.gov (United States)

    Blick, Mikkal G; Puchalski, Breann H; Bolanos, Veronica J; Wolfe, Kaitlin M; Green, Matthew C; Ryan, Bryce C

    2015-04-01

    Mouse models of autistic like behaviors are a valuable tool to use when studying the causes, symptoms, and potential treatments for autism. The inbred C58/J strain is a strain of interest for this model and has previously been shown to possess face validity for some of the core traits of autism, including low social behavior and elevated motor stereotypies. Higher order repetitive behaviors have not been extensively studied in this strain, or in mice in general. In this study, we looked for evidence of higher-order repetitive behaviors in the C58/J strain using a novel object assay. This assay utilized a mouse's natural exploratory behavior among unfamiliar objects to identify potential sequencing patterns in motor activity. The motor stereotypies displayed by the C58/J strain during testing were consistent with past studies. The C58/J strain also displayed a high preference for a single object in the round arena assays and the females demonstrating elevated sequencing patterns in the round arena. Although the C58/J strain did not show pervasive evidence of higher-order repetitive behaviors across all measures, there was evidence of higher order repetitive behaviors in certain situations. This study further demonstrates the potential of the C58/J mouse strains as a model for lower-order and potentially, higher-order repetitive behaviors. This study also demonstrates that the shape of the novel object arena can change the behavior displayed by the test animals. Further studies utilizing the C58/J strain and further validation of the novel object assay are warranted. PMID:25532914

  8. Interleukins in chronic liver disease: lessons learned from experimental mouse models

    Directory of Open Access Journals (Sweden)

    Hammerich L

    2014-09-01

    Full Text Available Linda Hammerich, Frank Tacke Department of Medicine III, University Hospital Aachen, Aachen, Germany Abstract: Interleukins represent a class of immunomodulatory cytokines, small intercellular signaling proteins, that are critically involved in the regulation of immune responses. They are produced in large amounts by various cell types during inflammatory reactions, and the balance of cytokines determines the outcome of an immune response. Therefore, cytokines are regarded as interesting therapeutic targets for the treatment of patients with liver diseases. Mouse models provide a good tool for in vivo studies on cytokine function, as human and mouse cytokines share many homologies. Sophisticated mouse models either mimicking distinct pathological conditions or targeting cytokines and cytokine-signaling pathways in the liver or even in distinct cellular compartments have provided enormous insight into the different functions of interleukins during hepatic inflammation. Interleukins may have pro- as well as anti-inflammatory functions in chronic liver diseases, some interleukins even both, dependent on the inflammatory stimulus, the producing and the responding cell type. IL-17, for example, promotes hepatic fibrogenesis through activation of hepatic stellate cells and facilitates development of liver cancer through recruitment of myeloid-derived suppressor cells. IL-22, on the other hand, protects from development of fibrosis or steatohepatitis. IL-12 balances T-helper (Th-1 and Th2 cell responses in infectious disease models. IL-13 and IL-33, two cytokines related to Th2 cells and innate lymphoid cells, promote fibrotic responses in the liver. IL-10 is the prototypic anti-inflammatory interleukin with tissue-protective functions during chronic liver injury and fibrogenesis. Despite its critical role for inducing the acute-phase response in the liver, IL-6 signaling is protective during fibrosis progression, but promotes hepatocellular carcinoma

  9. Fusion of the mouse IgG1 Fc domain to the VHH fragment (ARP1) enhances protection in a mouse model of rotavirus.

    Science.gov (United States)

    Günaydın, Gökçe; Yu, Shengze; Gräslund, Torbjörn; Hammarström, Lennart; Marcotte, Harold

    2016-01-01

    A variable fragment of a heavy chain antibody (VHH) directed against rotavirus, also referred to as anti-rotavirus protein 1 (ARP1), was shown to confer protection against rotavirus induced diarrhea in infant mouse model of rotavirus induced diarrhea. In this study, we have fused the mouse IgG1 Fc to ARP1 to improve the protective capacity of ARP1 by inducing an Fc-mediated effector function. We have shown that the Fc-ARP1 fusion protein confers significantly increased protection against rotavirus in a neonatal mouse model of rotavirus-induced diarrhea by reducing the prevalence, duration and severity of diarrhea and the viral load in the small intestines, suggesting that the Fc part of immunoglobulins may be engaged in Fc-mediated neutralization of rotavirus. Engineered conventional-like antibodies, by fusion of the Fc part of immunoglobulins to antigen-specific heavy-chain only VHH fragments, might be applied to novel antibody-based therapeutic approaches to enhance elimination of pathogens by activation of distinct effector signaling pathways. PMID:27439689

  10. Selecting the "right" mouse model for metabolic syndrome and type 2 diabetes research.

    Science.gov (United States)

    Leiter, Edward H

    2009-01-01

    This is not a "Methods" chapter in the traditional sense. Rather, it is an essay designed to help address one of the most frequently asked questions by investigators about to embark on a study requiring an animal model of diabetes - what is the "right" model for the reader's specific research application. Because genetic heterogeneity and the requirement for complex gene-environment interaction characterize the various mouse models of Type 2 diabetes as well as the human disease manifestations, the readers may come to share the author's conclusion that more than one model is required if the investigator is interested in knowing how broadly effective a given compound with putative therapeutic efficacy might be.

  11. Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis — A Literature Review

    Directory of Open Access Journals (Sweden)

    Leena Rivina

    2012-12-01

    Full Text Available As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus remains one of the best animal model systems for cancer research due to its molecular and physiological similarities to man, small size, ease of breeding in captivity and a fully sequenced genome. This work reviews relevant M. musculus inbred and F1 hybrid animal models and methodologies of induction of radiation-induced leukemia, thymic lymphoma, breast, and lung cancer in these models. Where available, the associated molecular pathologies are also included.

  12. Evidence of oxidative injury during aging of the liver in a mouse model.

    OpenAIRE

    Colantoni, Alessandra; Idilman, Ramazan; De Maria, Nicola; Duffner, Lisa A.; VAN THIEL, DAVID H.; Witte, Pamela L.; Kovacs, Elizabeth J.

    2001-01-01

    The aim of the present study was to determine whether oxidative stress contributes to aging of the liver in a mouse model. Liver was obtained from young (3–5 months old) and aged (18–24 months old) mice. No age-induced gross changes in liver morphology were detected by light microscopy. Apoptosis was measured using the fragment end labeling of DNA for the immunohistochemical identification of the apoptotic nuclei. The total apoptotic cells represented 1% of the total cells in livers of young ...

  13. Effects of IMOD™ and Angipars™ on mouse D-galactose-induced model of aging

    OpenAIRE

    Samane Ghanbari; Mahsa Yonessi; Azadeh Mohammadirad; Mahdi Gholami; Maryam Baeeri; Hamid Reza Khorram-Khorshid; Farhad Gharibdoost; Mohammad Abdollahi

    2012-01-01

    Abstract The aim of this study was to evaluate the effects of two registered herbal drugs called IMOD and Angipars on mouse model of. Aging was induced by D-galactose (500 mg/kg) administered to animals for 6 weeks through drinking water. Male BALB/c mice were randomly divided into 5 groups receiving D-galactose (D-galactose, 500 mg/kg) for 6 weeks; positive control (D-galactose [500 mg/kg] for 6 weeks + Vitamin E [200 mg/kg/day] intraperitoneally for 4 weeks); IMOD (D-galactose [500 mg/kg] f...

  14. Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model

    Science.gov (United States)

    Gabriel, Sherif E.; Brigman, Kristen N.; Koller, Beverly H.; Boucher, Richard C.; Stutts, M. Jackson

    1994-10-01

    The effect of the number of cystic fibrosis (CF) alleles on cholera toxin (CT)-induced intestinal secretion was examined in the CF mouse model. CF mice that expressed no CF transmembrane conductance regulator (CFTR) protein did not secrete fluid in response to CT. Heterozygotes expressed 50 percent of the normal amount of CFTR protein in the intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion in response to CT. This correlation between CFTR protein and CT-induced chloride ion and fluid secretion suggests that CF heterozygotes might possess a selective advantage of resistance to cholera.

  15. A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

    OpenAIRE

    Tai, S.J.; HERZOG, R. W.; MARGARITIS, P.; ARRUDA, V R; CHU, K; Golden, J A; LABOSKY, P A; High, K A

    2008-01-01

    Background:Activated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal. Objective:We sought to generate a viable mouse model of FX deficiency. Methods:We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10 tm1Ccmt, a...

  16. The S100A4 Oncoprotein Promotes Prostate Tumorigenesis in a Transgenic Mouse Model

    DEFF Research Database (Denmark)

    Siddique, Hifzur R; Adhami, Vaqar M; Parray, Aijaz;

    2013-01-01

    weights (P < 0.001). We generated S100A4-positive clones from S100A4-negative CaP cells and tested their potential. S100A4-positive tumors grew at a faster rate than S100A4-negative tumors in vitro and in a xenograft mouse model. The S100A4 protein exhibited growth factor-like properties in multimode....... Keeping in view its growth-promoting role, we suggest that S100A4 qualifies as an excellent candidate to be exploited for therapeutic agents to treat CaP in humans....

  17. Generating Mouse Models Using CRISPR-Cas9-Mediated Genome Editing.

    Science.gov (United States)

    Qin, Wenning; Kutny, Peter M; Maser, Richard S; Dion, Stephanie L; Lamont, Jeffrey D; Zhang, Yingfan; Perry, Greggory A; Wang, Haoyi

    2016-01-01

    The CRISPR-Cas9 system in bacteria and archaea has recently been exploited for genome editing in various model organisms, including mice. The CRISPR-Cas9 reagents can be delivered directly into the mouse zygote to derive a mutant animal carrying targeted genetic modifications. The major components of the system include the guide RNA, which provides target specificity, the Cas9 nuclease that creates the DNA double-strand break, and the donor oligonucleotide or plasmid carrying the intended mutation flanked by sequences homologous to the target site. Here we describe the general considerations and experimental protocols for creating genetically modified mice using the CRISPR-Cas9 system. PMID:26928663

  18. Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis

    OpenAIRE

    Pike, Lisa S.; Tannous, Bakhos A; Deliolanis, Nikolaos C.; Hsich, Gary; Morse, Danielle; Tung, Ching-Hsuan; Sena-Esteves, Miguel; Breakefield, Xandra O.

    2011-01-01

    Adeno-associated virus (AAV) mediated gene replacement for lysosomal disorders have been spurred by the ability of some serotypes to efficiently transduce neurons in the brain and by the ability of lysosomal enzymes to cross-correct among cells. Here, we explored enzyme replacement therapy in a knock-out mouse model of congenital neuronal ceroid lipofuscinosis (NCL), the most severe of the NCLs in humans. The missing protease in this disorder, cathepsin D (CathD) has high levels in the centra...

  19. Progression of Neuronal and Synaptic Remodeling in the rd10 Mouse Model of Retinitis Pigmentosa

    OpenAIRE

    Phillips, M. Joseph; Otteson, Deborah C.; David M Sherry

    2010-01-01

    The Pde6brd10 (rd10) mouse has a moderate rate of photoreceptor degeneration and serves as a valuable model for human autosomal recessive retinitis pigmentosa (RP). We evaluated the progression of neuronal remodeling of second- and third-order retinal cells and their synaptic terminals in retinas from Pde6brd10 (rd10) mice at varying stages of degeneration ranging from postnatal day 30 (P30) to postnatal month 9.5 (PNM9.5) using immunolabeling for well known cell- and synapse-specific markers...

  20. A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis

    OpenAIRE

    Xiaoyu Jiang; Liya Yuan; Engelbach, John A.; Jeremy Cates; Perez-Torres, Carlos J; Feng Gao; Dinesh Thotala; Drzymala, Robert E; Schmidt, Robert E.; Rich, Keith M.; Hallahan, Dennis E.; Ackerman, Joseph J.H.; Garbow, Joel R.

    2015-01-01

    Purpose To develop a Gamma Knife-based mouse model of late time-to-onset, cerebral radiation necrosis (RN) with serial evaluation by magnetic resonance imaging (MRI) and histology. Methods and Materials Mice were irradiated with the Leksell Gamma Knife® (GK) PerfexionTM (Elekta AB; Stockholm, Sweden) with total single-hemispheric radiation doses (TRD) of 45- to 60-Gy, delivered in one to three fractions. RN was measured using T2-weighted MR images, while confirmation of tissue damage was asse...

  1. Illuminating p53 function in cancer with genetically engineered mouse models

    OpenAIRE

    Garcia, Patty B.; Attardi, Laura D.

    2014-01-01

    The key role of the p53 protein in tumor suppression is highlighted by its frequent mutation in human cancers and by the completely penetrant cancer predisposition of p53 null mice. Beyond providing definitive evidence for the critical function of p53 in tumor suppression, genetically engineered mouse models have offered numerous additional insights into p53 function. p53 knock-in mice expressing tumor-derived p53 mutants have revealed that these mutants display gain-of-function activities th...

  2. Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer’s disease

    OpenAIRE

    Ho, Angela; Liu, Xinran; Südhof, Thomas C.

    2008-01-01

    Mints/X11s are neuronal adaptor proteins that bind to amyloid-β precursor protein (APP). Previous studies suggested that Mint/X11 proteins influence APP cleavage, and affect production of pathogenic Aβ-peptides in Alzheimer’s disease; however, the biological significance of Mint/X11-binding to APP and their possible role in Aβ-production remain unclear. Here, we crossed conditional and constitutive Mint1, Mint2, and Mint3 knockout mice with transgenic mouse models of Alzheimer’s disease overp...

  3. Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer's Disease Mouse Model.

    Science.gov (United States)

    Manousopoulou, Antigoni; Saito, Satoshi; Yamamoto, Yumi; Al-Daghri, Nasser M; Ihara, Masafumi; Carare, Roxana O; Garbis, Spiros D

    2016-01-01

    The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.

  4. Amniotic Epithelial Cells from the Human Placenta Potently Suppress a Mouse Model of Multiple Sclerosis

    OpenAIRE

    Yu Han Liu; Vijesh Vaghjiani; Jing Yang Tee; Kelly To; Peng Cui; Ding Yuan Oh; Ursula Manuelpillai; Ban-Hock Toh; James Chan

    2012-01-01

    Human amniotic epithelial cells (hAEC) have stem cell-like features and immunomodulatory properties. Here we show that hAEC significantly suppressed splenocyte proliferation in vitro and potently attenuated a mouse model of multiple sclerosis (MS). Central nervous system (CNS) CD3(+) T cell and F4/80(+) monocyte/macrophage infiltration and demyelination were significantly reduced with hAEC treatment. Besides the known secretion of prostaglandin E2 (PGE2), we report the novel finding that hAEC...

  5. Pingchuan formula improves asthma via restoration of the Th17/Treg balance in a mouse model

    OpenAIRE

    Liu, Fei; Yu, Jianer; Bai, Li; Xue, Zheng; Zhang, Xinguang

    2015-01-01

    Background Pingchuan Formula (PCF) is a traditional Chinese recipe. PCF improves chronic airway inflammation by correcting the imbalance of T-helper cell ratio. The purpose of this study was to investigate the effect of PCF on pathological changes in the lungs of asthmatic mice in terms of Treg/Th17 balance. Methods A bronchial asthma BALB/c mouse model was established using the ovalbumin excitation method. Distilled water (for MDL group) and drugs (for DEX or PCF group) were administered by ...

  6. Hormetic Effect of Chronic Hypergravity in a Mouse Model of Allergic Asthma and Rhinitis

    OpenAIRE

    Tae Young Jang; Ah-Yeoun Jung; Young Hyo Kim

    2016-01-01

    We aimed to evaluate the effect of chronic hypergravity in a mouse model of allergic asthma and rhinitis. Forty BALB/c mice were divided as: group A (n = 10, control) sensitized and challenged with saline, group B (n = 10, asthma) challenged by intraperitoneal and intranasal ovalbumin (OVA) to induce allergic asthma and rhinitis, and groups C (n = 10, asthma/rotatory control) and D (n = 10, asthma/hypergravity) exposed to 4 weeks of rotation with normogravity (1G) or hypergravity (5G) during ...

  7. Hypothalamus transcriptome profile suggests an anorexia-cachexia syndrome in the anx/anx mouse model

    OpenAIRE

    Mercader Bigas, Josep Maria; Lozano, Juan Jos??; Sumoy, Lauro; Dierssen, Mara; Visa, Joana; Gratac??s Mayora, M??nica; Estivill, Xavier

    2008-01-01

    The anx/anx mouse displays poor appetite and lean appearance and is considered a good model for the study of anorexia nervosa. To identify new genes involved in feeding behavior and body weight regulation we performed an expression profiling in the hypothalamus of the anx/anx mice. Using commercial microarrays we detected 156 differentially expressed genes and validated 92 of those using TaqMan low-density arrays. The expression of a set of 87 candidate genes selected based on literature evid...

  8. Peripheral nervous system manifestations in a Sandhoff disease mouse model: nerve conduction, myelin structure, lipid analysis

    OpenAIRE

    Strichartz Gary R; Seyfried Thomas N; Avila Robin L; Baek Rena C; McNally Melanie A; Kirschner Daniel A

    2007-01-01

    Abstract Background Sandhoff disease is an inherited lysosomal storage disease caused by a mutation in the gene for the β-subunit (Hexb gene) of β-hexosaminidase A (αβ) and B (ββ). The β-subunit together with the GM2 activator protein catabolize ganglioside GM2. This enzyme deficiency results in GM2 accumulation primarily in the central nervous system. To investigate how abnormal GM2 catabolism affects the peripheral nervous system in a mouse model of Sandhoff disease (Hexb-/-), we examined t...

  9. Virulence of different Pseudomonas species in a burned mouse model: tissue colonization by Pseudomonas cepacia.

    OpenAIRE

    Stover, G B; Drake, D R; Montie, T C

    1983-01-01

    The virulence of Pseudomonas aeruginosa and other pseudomonads was examined in a burned mouse model. P. aeruginosa M-2 was highly virulent causing 100% mortality by 38 h with an injection of 10(2) CFU by either a subcutaneous or intraperitoneal route. Subcutaneous injection of 10(2) CFU revealed rapid multiplication of the bacteria at the burn wound with 10(8) CFU/g detectable in the burned skin by 28 h postinjection, 10(5) CFU/g of liver, and 10(3) CFU/ml of blood. Non-P. aeruginosa clinical...

  10. Magnetic Nanoparticle-Based Hyperthermia for Head & Neck Cancer in Mouse Models

    Directory of Open Access Journals (Sweden)

    Qun Zhao, Luning Wang, Rui Cheng, Leidong Mao, Robert D. Arnold, Elizabeth W. Howerth, Zhuo G. Chen, Simon Platt

    2012-01-01

    Full Text Available In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line. A hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields. Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect. Experimental results showed that the temperature of the tumor center has dramatically elevated from around the room temperature to about 40oC within the first 5-10 minutes. Pathological studies demonstrate epithelial tumor cell destruction associated with the hyperthermia treatment.

  11. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy.

    Science.gov (United States)

    Dong, Han-Yu; Jiang, Xin-Mei; Niu, Chun-Bo; Du, Lin; Feng, Jun-Yan; Jia, Fei-Yong

    2016-01-01

    To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus. PMID:26981106

  12. Therapeutic potentials of human adipose-derived stem cells on the mouse model of Parkinson's disease.

    Science.gov (United States)

    Choi, Hee Soon; Kim, Hee Jin; Oh, Jin-Hwan; Park, Hyeong-Geun; Ra, Jeong Chan; Chang, Keun-A; Suh, Yoo-Hun

    2015-10-01

    The treatment of Parkinson's disease (PD) using stem cells has long been the focus of many researchers, but the ideal therapeutic strategy has not yet been developed. The consistency and high reliability of the experimental results confirmed by animal models are considered to be a critical factor in the stability of stem cell transplantation for PD. Therefore, the aim of this study was to investigate the preventive and therapeutic potential of human adipose-derived stem cells (hASC) for PD and was to identify the related factors to this therapeutic effect. The hASC were intravenously injected into the tail vein of a PD mouse model induced by 6-hydroxydopamine. Consequently, the behavioral performances were significantly improved at 3 weeks after the injection of hASC. Additionally, dopaminergic neurons were rescued, the number of structure-modified mitochondria was decreased, and mitochondrial complex I activity was restored in the brains of the hASC-injected PD mouse model. Overall, this study underscores that intravenously transplanted hASC may have therapeutic potential for PD by recovering mitochondrial functions.

  13. Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus.

    Science.gov (United States)

    Elshikha, Ahmed S; Lu, Yuanqing; Chen, Mong-Jen; Akbar, Mohammad; Zeumer, Leilani; Ritter, Andrea; Elghamry, Hanaa; Mahdi, Mahmoud A; Morel, Laurence; Song, Sihong

    2016-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupus-prone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans. PMID:27232337

  14. Novel mouse model of spinal cord injury-induced heterotopic ossification

    Directory of Open Access Journals (Sweden)

    Heejae Kang, BA

    2014-11-01

    Full Text Available Heterotopic ossification (HO develops in about 20% to 30% of patients with spinal cord injury (SCI and significantly impairs their rehabilitation. There is no effective prevention or treatment for this condition at this time. Our current understanding of its etiology and pathophysiology is limited partially due to the lack of clinically relevant animal models. In this study, we report a novel mouse model of SCI-induced HO by administering a subthreshold dose of bone morphogenetic protein (BMP-2 to muscles in mice after SCI. Microcomputed tomography scanning showed that an intramuscular injection of 0.25 micrograms of BMP-2 causes significant HO in mice with SCI but not in control (sham surgery mice. Our analysis of gene expression showed significantly increased BMP signaling in quadriceps following SCI, suggesting that BMP signaling may play a role in SCI-induced HO. Administering 0.25 micrograms of BMP-2 to the front arms of the mice with SCI also results in the development of significant HO but not in control mice. This suggests that SCI causes a systematic osteogenic effect, which is not limited to paralyzed limbs. This novel mouse model will serve as a powerful tool in exploring the molecular mechanisms of SCI-induced HO, which may lead to novel treatment for this disease.

  15. An improved intrafemoral injection with minimized leakage as an orthotopic mouse model of osteosarcoma

    Science.gov (United States)

    Sasaki, Hiromi; Iyer, Swathi V.; Sasaki, Ken; Tawfik, Ossama W.; Iwakuma, Tomoo

    2015-01-01

    Osteosarcoma, the most common type of primary bone cancer, is the second highest cause of cancer-related death in pediatric patients. To understand the mechanisms behind osteosarcoma progression and to discover novel therapeutic strategies for this disease, a reliable and appropriate mouse model is essential. For this purpose, osteosarcoma cells need to be injected into the bone marrow. Previously, the intratibial and intrafemoral injection methods were reported; however, the major drawback of these methods is the potential leakage of tumor cells from the injection site during or after these procedures. To overcome this, we have established an improved method to minimize leakage in an orthotopic mouse model of osteosarcoma. By taking advantage of the anatomical benefits of the femur with less bowing and larger medullary cavity than those of the tibia, osteosarcoma cells are injected directly into the femoral cavity following reaming of its intramedullary space. To prevent potential leakage of tumor cells during and after the surgery, the injection site is sealed with bone wax. This method requires a minor surgery of approximately 15 minutes under anesthesia. Our established orthotopic osteosarcoma model could serve as a valuable and reliable tool for examining tumor progression of various types of bone tumors. PMID:26142221

  16. Longitudinal assessment of in vivo bone dynamics in a mouse tail model of postmenopausal osteoporosis.

    Science.gov (United States)

    Lambers, Floor M; Kuhn, Gisela; Schulte, Friederike A; Koch, Kathleen; Müller, Ralph

    2012-02-01

    Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6 mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6 mice were ovariectomized (OVX, n = 11) or sham-operated (SHM, n = 9) and monitored with in vivo μCT on the day of surgery and every 2 weeks after, up to 12 weeks. There was a significant decrease in bone volume fraction for OVX (-35%) compared to SHM (+16%) in trabecular bone (P bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P bone stiffness for OVX (-16%) compared to SHM (+11%, P tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P bone formation rate (P bone biology is a promising method for future research.

  17. Mouse models of Mdm2 and Mdm4 and their clinical implications

    Institute of Scientific and Technical Information of China (English)

    Shunbin Xiong

    2013-01-01

    Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 induces p53-dependent apoptosis,whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest.Compared to Mdm4 deletion,Mdm2 deletion causes more severe phenotypic defects.Disrupting the Mdm2 and Mdm4 interaction using knockin mice models causes embryonic lethality that can be completely rescued by the concomitant loss of p53,suggesting that Mdm2 and Mdm4 heterodimerization is critical to inhibit p53 activity during embryogenesis.Overexpression of Mdm2 and Mdm4 in mice induces spontaneous tumorigenesis,which clearly indicates that Mdm2 and Mdm4 are bona fide oncogenes.Studies from these mouse models strongly suggest that blocking Mdm2-and Mdm4-mediated p53 inhibition is an appealing therapeutic strategy for cancer patients with wild-type p53 alleles.

  18. Chemokine-Targeted Mouse Models of Human Primary and Metastatic Colorectal Cancer

    Science.gov (United States)

    Chen, Huanhuan Joyce; Sun, Jian; Huang, Zhiliang; Hou, Harry; Arcilla, Myra; Rakhilin, Nikolai; Joe, Daniel J.; Choi, Jiahn; Gadamsetty, Poornima; Milsom, Jeff; Nandakumar, Govind; Longman, Randy; Zhou, Xi Kathy; Edwards, Robert; Chen, Jonlin; Chen, Kai Yuan; Bu, Pengcheng; Wang, Lihua; Xu, Yitian; Munroe, Robert; Abratte, Christian; Miller, Andrew D.; Gümüş, Zeynep H.; Shuler, Michael; Nishimura, Nozomi; Edelmann, Winfried; Shen, Xiling; Lipkin, Steven M.

    2015-01-01

    Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired sub-cutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening. PMID:26006007

  19. Role of FGF/FGFR signaling in skeletal development and homeostasis:learning from mouse models

    Institute of Scientific and Technical Information of China (English)

    Nan Su; Min Jin; Lin Chen

    2014-01-01

    Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-in/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis.

  20. Tau reduction does not prevent motor deficits in two mouse models of Parkinson's disease.

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    Meaghan Morris

    Full Text Available Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD and Parkinson's disease (PD. Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau(+/+, Tau(+/- and Tau(-/- backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and that tau reduction may not be of benefit in the latter condition.

  1. Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three-Dimensional Ultrasound Imaging Technique.

    Science.gov (United States)

    Ni, Jie; Cozzi, Paul; Hung, Tzong-Tyng; Hao, Jingli; Graham, Peter; Li, Yong

    2016-02-01

    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; r(2) = 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 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.

  2. Efficacious intermittent dosing of a novel JAK2 inhibitor in mouse models of polycythemia vera.

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    Manfred Kraus

    Full Text Available A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2 gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.

  3. Mouse lung infection model to assess Rhodococcus equi virulence and vaccine protection.

    Science.gov (United States)

    González-Iglesias, Patricia; Scortti, Mariela; MacArthur, Iain; Hapeshi, Alexia; Rodriguez, Héctor; Prescott, John F; Vazquez-Boland, José A

    2014-08-01

    The pathogenic actinomycete Rhodococcus equi causes severe purulent lung infections in foals and immunocompromised people. Although relatively unsusceptible to R. equi, mice are widely used for in vivo studies with this pathogen. The most commonly employed mouse model is based on systemic (intravenous) infection and determination of R. equi burdens in spleen and liver. Here, we investigated the murine lung for experimental infection studies with R. equi. Using a 10(7)CFU intranasal challenge in BALB/c mice, virulent R. equi consistently survived in quantifiable numbers up to 10 days in the lungs whereas virulence-deficient R. equi bacteria were rapidly cleared. An internally controlled virulence assay was developed in which the test R. equi strains are co-inoculated and monitored in the same mouse. Isogenic R. equi bacteria lacking either the plasmid vapA gene or the entire virulence plasmid were compared using this competitive assay. Both strains showed no significant differences in in vivo fitness in the lung, indicating that the single loss of the virulence factor VapA was sufficient to account for the full attenuation seen in the absence of the virulence plasmid. To test the adequacy of the lung infection model for monitoring R. equi vaccine efficacy, BALB/c mice were immunized with live R. equi and challenged intranasally. Vaccination conferred protection against acute pulmonary challenge with virulent R. equi. Our data indicate that the murine lung infection model provides a useful tool for both R. equi virulence and vaccine studies. PMID:24852140

  4. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy.

    Science.gov (United States)

    Dong, Han-Yu; Jiang, Xin-Mei; Niu, Chun-Bo; Du, Lin; Feng, Jun-Yan; Jia, Fei-Yong

    2016-01-01

    To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

  5. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

    Institute of Scientific and Technical Information of China (English)

    Han-yu Dong; Xin-mei Jiang; Chun-bo Niu; Lin Du; Jun-yan Feng; Fei-yong Jia

    2016-01-01

    To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

  6. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Han-yu Dong

    2016-01-01

    Full Text Available To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position, prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds, and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

  7. Granulocytes and vascularization regulate uterine bleeding and tissue remodeling in a mouse menstruation model.

    Directory of Open Access Journals (Sweden)

    Astrid Menning

    Full Text Available Menstruation-associated disorders negatively interfere with the quality of life of many women. However, mechanisms underlying pathogenesis of menstrual disorders remain poorly investigated up to date. Among others, this is based on a lack of appropriate pre-clinical animal models. We here employ a mouse menstruation model induced by priming mice with gonadal hormones and application of a physical stimulus into the uterus followed by progesterone removal. As in women, these events are accompanied by menstrual-like bleeding and tissue remodeling processes, i.e. disintegration of decidualized endometrium, as well as subsequent repair. We demonstrate that the onset of bleeding coincides with strong upregulation of inflammatory mediators and massive granulocyte influx into the uterus. Uterine granulocytes play a central role in regulating local tissue remodeling since depletion of these cells results in dysregulated expression of matrix modifying enzymes. As described here for the first time, uterine blood loss can be quantified by help of tampon-like cotton pads. Using this novel technique, we reveal that blood loss is strongly reduced upon inhibition of endometrial vascularization and thus, is a key regulator of menstrual bleeding. Taken together, we here identify angiogenesis and infiltrating granulocytes as critical determinants of uterine bleeding and tissue remodeling in a mouse menstruation model. Importantly, our study provides a technical and scientific basis allowing quantification of uterine blood loss in mice and thus, assessment of therapeutic intervention, proving great potential for future use in basic research and drug discovery.

  8. Polydimethylsiloxane embedded mouse aorta ex vivo perfusion model: proof-of-concept study focusing on atherosclerosis.

    Science.gov (United States)

    Wang, Xueya; Wolf, Marc P; Keel, Rahel Bänziger; Lehner, Roman; Hunziker, Patrick R

    2012-07-01

    Existing mouse artery ex vivo perfusion models have utilized arteries such as carotid, uterine, and mesenteric arteries, but not the aorta. However, the aorta is the principal vessel analyzed for atherosclerosis studies in vivo. We have devised a mouse aorta ex vivo perfusion model that can bridge this gap. Aortas from apoE((-/-)) mice are embedded in a transparent, gas-permeable, and elastic polymer matrix [polydimethylsiloxane (PDMS)] and artificially perfused with cell culture medium under cell culture conditions. After 24 h of artificial ex vivo perfusion, no evidence of cellular apoptosis is detected. Utilizing a standard confocal microscope, it is possible to image specific receptor targeting of cells in atherosclerotic plaques during 24 h. Imaging motion artifacts are minimal due to the polymer matrix embedding. Re-embedding of the aorta enables tissue sectioning and immuno-histochemical analysis. The ex vivo data are validated by comparison with in vivo experiments. This model can save animal lives via production of multiple endpoints in a single experiment, is easy to apply, and enables straightforward comparability with pre-existing atherosclerosis in vivo data. It is suited to investigate atherosclerotic disease in particular and vascular biology in general.

  9. Ghrelin and eating behavior: evidence and insights from genetically-modified mouse models

    Directory of Open Access Journals (Sweden)

    Aki eUchida

    2013-07-01

    Full Text Available Ghrelin is an octanoylated peptide hormone, produced by endocrine cells of the stomach, which acts in the brain to increase food intake and body weight. Our understanding of the mechanisms underlying ghrelin’s effects on eating behaviors has been greatly improved by the generation and study of several genetically manipulated mouse models.These models include mice overexpressing ghrelin and also mice with genetic deletion of ghrelin, the ghrelin receptor [the growth hormone secretagogue receptor (GHSR] or the enzyme that post-translationally modifies ghrelin [ghrelin O-acyltransferase (GOAT]. In addition, a GHSR-null mouse model in which GHSR transcription is globally blocked but can be cell-specifically reactivated in a Cre recombinase-mediated fashion has been generated. Here, we summarize findings obtained with these genetically manipulated mice, with the aim to highlight the significance of the ghrelin system in the regulation of both homeostatic and hedonic eating, including that occurring in the setting of chronic psychosocial stress.

  10. White Adipose Tissue Browning in the R6/2 Mouse Model of Huntington's Disease.

    Science.gov (United States)

    McCourt, Andrew C; Jakobsson, Lovisa; Larsson, Sara; Holm, Cecilia; Piel, Sarah; Elmér, Eskil; Björkqvist, Maria

    2016-01-01

    Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disorder, characterised not only by progressive cognitive, motor and psychiatric impairments, but also of peripheral pathology. In both human HD and in mouse models of HD there is evidence of increased energy expenditure and weight loss, alongside altered body composition. Unlike white adipose tissue (WAT), brown adipose tissue (BAT), as well as brown-like cells within WAT, expresses the mitochondrial protein, uncoupling protein 1 (UCP1). UCP1 enables dissociation of cellular respiration from ATP utilization, resulting in the release of stored energy as heat. Hyperplasia of brown/beige cells in WAT has been suggested to enhance energy expenditure. In this study, we therefore investigated the gene expression profile, histological appearance, response to cold challenge and functional aspects of WAT in the R6/2 HD mouse model and selected WAT gene expression in the full-length Q175 mouse model of HD. WAT from R6/2 mice contained significantly more brown-like adipocyte regions and had a gene profile suggestive of the presence of brown-like adipocytes, such as higher Ucp1 expression. Cold exposure induced Ucp1 expression in R6/2 inguinal WAT to a markedly higher degree as compared to the thermogenic response in WT WAT. Alongside this, gene expression of transcription factors (Zfp516 and Pparα), important inducers of WAT browning, were increased in R6/2 inguinal WAT, and Creb1 was highlighted as a key transcription factor in HD. In addition to increased WAT Ucp1 expression, a trend towards increased mitochondrial oxygen consumption due to enhanced uncoupling activity was found in inguinal R6/2 WAT. Key gene expressional changes (increased expression of (Zfp516 and Pparα)) were replicated in inguinal WAT obtained from Q175 mice. In summary, for the first time, we here show that HD mouse WAT undergoes a process of browning, resulting in molecular and functional alterations that may

  11. Establishment of Early Endpoints in Mouse Total-Body Irradiation Model

    Science.gov (United States)

    Gulani, Jatinder; King, Gregory; Hieber, Kevin; Chappell, Mark; Ossetrova, Natalia

    2016-01-01

    Acute radiation sickness (ARS) following exposure to ionizing irradiation is characterized by radiation-induced multiorgan dysfunction/failure that refers to progressive dysfunction of two or more organ systems, the etiological agent being radiation damage to cells and tissues over time. Radiation sensitivity data on humans and animals has made it possible to describe the signs associated with ARS. A mouse model of total-body irradiation (TBI) has previously been developed that represents the likely scenario of exposure in the human population. Herein, we present the Mouse Intervention Scoring System (MISS) developed at the Veterinary Sciences Department (VSD) of the Armed Forces Radiobiology Research Institute (AFRRI) to identify moribund mice and decrease the numbers of mice found dead, which is therefore a more humane refinement to death as the endpoint. Survival rates were compared to changes in body weights and temperatures in the mouse (CD2F1 male) TBI model (6–14 Gy, 60Co γ-rays at 0.6 Gy min-1), which informed improvements to the Scoring System. Individual tracking of animals via implanted microchips allowed for assessment of criteria based on individuals rather than by group averages. From a total of 132 mice (92 irradiated), 51 mice were euthanized versus only four mice that were found dead (7% of non-survivors). In this case, all four mice were found dead after overnight periods between observations. Weight loss alone was indicative of imminent succumbing to radiation injury, however mice did not always become moribund within 24 hours while having weight loss >30%. Only one survivor had a weight loss of greater than 30%. Temperature significantly dropped only 2–4 days before death/euthanasia in 10 and 14 Gy animals. The score system demonstrates a significant refinement as compared to using subjective assessment of morbidity or death as the endpoint for these survival studies. PMID:27579862

  12. An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.

    Science.gov (United States)

    Zhang, Shuang; Johnson, Christopher M; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Wu, Yang; Jiang, Chun

    2016-10-01

    Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc. PMID:27317352

  13. An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.

    Science.gov (United States)

    Zhang, Shuang; Johnson, Christopher M; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Wu, Yang; Jiang, Chun

    2016-10-01

    Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc.

  14. Establishment of Early Endpoints in Mouse Total-Body Irradiation Model.

    Science.gov (United States)

    Koch, Amory; Gulani, Jatinder; King, Gregory; Hieber, Kevin; Chappell, Mark; Ossetrova, Natalia

    2016-01-01

    Acute radiation sickness (ARS) following exposure to ionizing irradiation is characterized by radiation-induced multiorgan dysfunction/failure that refers to progressive dysfunction of two or more organ systems, the etiological agent being radiation damage to cells and tissues over time. Radiation sensitivity data on humans and animals has made it possible to describe the signs associated with ARS. A mouse model of total-body irradiation (TBI) has previously been developed that represents the likely scenario of exposure in the human population. Herein, we present the Mouse Intervention Scoring System (MISS) developed at the Veterinary Sciences Department (VSD) of the Armed Forces Radiobiology Research Institute (AFRRI) to identify moribund mice and decrease the numbers of mice found dead, which is therefore a more humane refinement to death as the endpoint. Survival rates were compared to changes in body weights and temperatures in the mouse (CD2F1 male) TBI model (6-14 Gy, 60Co γ-rays at 0.6 Gy min-1), which informed improvements to the Scoring System. Individual tracking of animals via implanted microchips allowed for assessment of criteria based on individuals rather than by group averages. From a total of 132 mice (92 irradiated), 51 mice were euthanized versus only four mice that were found dead (7% of non-survivors). In this case, all four mice were found dead after overnight periods between observations. Weight loss alone was indicative of imminent succumbing to radiation injury, however mice did not always become moribund within 24 hours while having weight loss >30%. Only one survivor had a weight loss of greater than 30%. Temperature significantly dropped only 2-4 days before death/euthanasia in 10 and 14 Gy animals. The score system demonstrates a significant refinement as compared to using subjective assessment of morbidity or death as the endpoint for these survival studies.

  15. The Applicability of a Human Immunohistochemical Panel to Mouse Models of Hepatocellular Neoplasia.

    Science.gov (United States)

    Salleng, Kenneth J; Revetta, Frank L; Deane, Natasha G; Washington, M Kay

    2015-10-01

    Various immunohistochemical panels are used as aids to distinguish between primary hepatocellular malignancies and metastatic tumors and between benign lesions and carcinomas. We compared the immunohistochemical spectrum of hepatocellular lesions in mice with that of human hepatocellular carcinoma (HCC). Specifically, we compared the staining parameters of 128 murine foci of cellular alteration (FCA) and tumors (adenoma and HCC) from archival tissue blocks of 3 transgenic mouse models (LFABP-cyclin D1, Alb1-TGFβ1, and LFABP-cyclin D1 × Alb1-TGFβ1) with those of archival human HCC (n = 5). Antibodies were chosen according to their published performance and characterization in human hepatocellular tumor diagnosis and included: arginase 1 (Arg1), β-catenin, glutamine synthetase (GS), glypican 3, hepatocyte paraffin 1 (HepPar1), and cytokeratin 19 (CK19). GS was the single best immunostain for identifying hepatocellular tumors in mice, with 100% positive staining. Data showed a trend toward loss of normal function (staining) with Arg1, with a higher percentage of positive staining in FCA than in adenomas and HCC. All FCA lacked murine β-catenin nuclear translocation, which was present in 2 of the 7 adenomas and 22 of the 96 HCC tested. HepPar1 staining was lower than anticipated, except in trabecular HCC (16 of 22 samples were positive). Glyp3 stained very lightly, and only scattered CK19-positive cells were noted (4 of 44 cases of mouse trabecular HCC). Thus, GS appears to be the most useful marker for identifying neoplasia in the transgenic mouse models we tested and should be included in immunohistochemistry assessing hepatocellular neoplasia development. PMID:26473343

  16. Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency

    Science.gov (United States)

    Vermeij, Wilbert P.; Tresini, Maria; Weymaere, Michael; Menoni, Hervé; Brandt, Renata M. C.; de Waard, Monique C.; Botter, Sander M.; Sarker, Altaf H.; Jaspers, Nicolaas G. J.; van der Horst, Gijsbertus T. J.; Cooper, Priscilla K.; Hoeijmakers, Jan H. J.; van der Pluijm, Ingrid

    2014-01-01

    As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg−/− mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging. PMID:25299392

  17. Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

    Directory of Open Access Journals (Sweden)

    Atkinson Mark A

    2011-02-01

    Full Text Available Abstract Background Alpha-1 antitrypsin (AAT is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA, a mouse model of rheumatoid arthritis (RA. Methods DBA/1 mice were immunized with bovine type II collagen (bCII to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT. Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF, antibodies against both bovine (bCII and mouse collagen II (mCII were tested by ELISA. Results Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially. Conclusion These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.

  18. A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis.

    Directory of Open Access Journals (Sweden)

    Xiaoyu Jiang

    Full Text Available To develop a Gamma Knife-based mouse model of late time-to-onset, cerebral radiation necrosis (RN with serial evaluation by magnetic resonance imaging (MRI and histology.Mice were irradiated with the Leksell Gamma Knife® (GK PerfexionTM (Elekta AB; Stockholm, Sweden with total single-hemispheric radiation doses (TRD of 45- to 60-Gy, delivered in one to three fractions. RN was measured using T2-weighted MR images, while confirmation of tissue damage was assessed histologically by hematoxylin & eosin, trichrome, and PTAH staining.MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation. The development of RN is significantly slower in mice irradiated with 45-Gy than 50- or 60-Gy, where RN development is similar. Irradiated mouse brains demonstrate all of the pathologic features observed clinically in patients with confirmed RN. A semi-quantitative (0 to 3 histologic grading system, capturing both the extent and severity of injury, is described and illustrated. Tissue damage, as assessed by a histologic score, correlates well with total necrotic volume measured by MRI (correlation coefficient = 0.948, with p<0.0001, and with post-irradiation time (correlation coefficient = 0.508, with p<0.0001.Following GK irradiation, mice develop late time-to-onset cerebral RN histology mirroring clinical observations. MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score. This mouse model of RN will provide a platform for mechanism of action studies, the identification of imaging biomarkers of RN, and the development of clinical studies for improved mitigation and neuroprotection.

  19. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

    International Nuclear Information System (INIS)

    Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH

  20. A humanized mouse model of hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia.

    Science.gov (United States)

    Lee, Seong Min; Goellner, Joseph J; O'Brien, Charles A; Pike, J Wesley

    2014-11-01

    The syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a genetic disease of altered mineral homeostasis due to mutations in the vitamin D receptor (VDR) gene. It is frequently, but not always, accompanied by the presence of alopecia. Mouse models that recapitulate this syndrome have been prepared through genetic deletion of the Vdr gene and are characterized by the presence of rickets and alopecia. Subsequent studies have revealed that VDR expression in hair follicle keratinocytes protects against alopecia and that this activity is independent of the protein's ability to bind 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In the present study, we introduced into VDR-null mice a human VDR (hVDR) bacterial artificial chromosome minigene containing a mutation that converts leucine to serine at amino acid 233 in the hVDR protein, which prevents 1,25(OH)2D3 binding. We then assessed whether this transgene recreated features of the HVDRR syndrome without alopecia. RT-PCR and Western blot analysis in one strain showed an appropriate level of mutant hVDR expression in all tissues examined including skin. The hVDR-L233S mutant failed to rescue the aberrant systemic and skeletal phenotype characteristic of the VDR null mouse due to the inability of the mutant receptor to activate transcription after treatment with 1,25(OH)2D3. Importantly, however, neither alopecia nor the dermal cysts characteristic of VDR-null mice were observed in the skin of these hVDR-L233S mutant mice. This study confirms that we have created a humanized mouse model of HVDRR without alopecia that will be useful in defining additional features of this syndrome and in identifying potential novel functions of the unoccupied VDR.

  1. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de [Department for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig (Germany)

    2014-08-15

    Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.

  2. Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis

    International Nuclear Information System (INIS)

    Immunohistochemical methods have been widely used to determine the histogenesis of spontaneous and chemically-induced mouse lung tumors. Typically, antigens for either alveolar Type II cells or bronchiolar epithelial Clara cells are studied. In the present work, the morphological and immunohistochemical phenotype of a transgenic mouse designed to develop lung tumors arising from Clara cells was evaluated. In this model, Clara cell-specific transformation is accomplished by directed expression of the SV40 large T antigen (TAg) under the mouse Clara cell secretory protein (CC10) promoter. In heterozygous mice, early lesions at 1 month of age consisted of hyperplastic bronchiolar epithelial cells. These progressed to adenoma by 2 months as proliferating epithelium extended into adjacent alveolar spaces. By 4 months, a large portion of the lung parenchyma was composed of tumor masses. Expression of constitutive CC10 was diminished in transgenic animals at all time points. Only the occasional cell or segment of the bronchiolar epithelium stained positively for CC10 by immunohistochemistry, and all tumors were found to be uniformly negative for staining. These results were corroborated by Western blotting, where CC10 was readily detectable in whole lung homogenate from nontransgenic animals, but not detected in lung from transgenic animals at any time point. Tumors were also examined for expression of surfactant apoprotein C (SPC), an alveolar Type II cell-specific marker, and found to be uniformly negative for staining. These results indicate that, in this transgenic model, expression of CC10, which is widely used to determine whether lung tumors arise from Clara cells, was reduced and subsequently lost during Clara cell tumor progression

  3. Establishment of Early Endpoints in Mouse Total-Body Irradiation Model.

    Science.gov (United States)

    Koch, Amory; Gulani, Jatinder; King, Gregory; Hieber, Kevin; Chappell, Mark; Ossetrova, Natalia

    2016-01-01

    Acute radiation sickness (ARS) following exposure to ionizing irradiation is characterized by radiation-induced multiorgan dysfunction/failure that refers to progressive dysfunction of two or more organ systems, the etiological agent being radiation damage to cells and tissues over time. Radiation sensitivity data on humans and animals has made it possible to describe the signs associated with ARS. A mouse model of total-body irradiation (TBI) has previously been developed that represents the likely scenario of exposure in the human population. Herein, we present the Mouse Intervention Scoring System (MISS) developed at the Veterinary Sciences Department (VSD) of the Armed Forces Radiobiology Research Institute (AFRRI) to identify moribund mice and decrease the numbers of mice found dead, which is therefore a more humane refinement to death as the endpoint. Survival rates were compared to changes in body weights and temperatures in the mouse (CD2F1 male) TBI model (6-14 Gy, 60Co γ-rays at 0.6 Gy min-1), which informed improvements to the Scoring System. Individual tracking of animals via implanted microchips allowed for assessment of criteria based on individuals rather than by group averages. From a total of 132 mice (92 irradiated), 51 mice were euthanized versus only four mice that were found dead (7% of non-survivors). In this case, all four mice were found dead after overnight periods between observations. Weight loss alone was indicative of imminent succumbing to radiation injury, however mice did not always become moribund within 24 hours while having weight loss >30%. Only one survivor had a weight loss of greater than 30%. Temperature significantly dropped only 2-4 days before death/euthanasia in 10 and 14 Gy animals. The score system demonstrates a significant refinement as compared to using subjective assessment of morbidity or death as the endpoint for these survival studies. PMID:27579862

  4. p38 mediates mechanical allodynia in a mouse model of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Hong Yu

    2010-05-01

    Full Text Available Abstract Background Painful Diabetic Neuropathy (PDN affects more than 25% of patients with type 2 diabetes; however, the pathogenesis remains unclear due to lack of knowledge of the molecular mechanisms leading to PDN. In our current study, we use an animal model of type 2 diabetes in order to understand the roles of p38 in PDN. Previously, we have demonstrated that the C57BLK db/db (db/db mouse, a model of type 2 diabetes that carries the loss-of-function leptin receptor mutant, develops mechanical allodynia in the hind paws during the early stage (6-12 wk of age of diabetes. Using this timeline of PDN, we can investigate the signaling mechanisms underlying mechanical allodynia in the db/db mouse. Results We studied the role of p38 in lumbar dorsal root ganglia (LDRG during the development of mechanical allodynia in db/db mice. p38 phosphorylation was detected by immunoblots at the early stage of mechanical allodynia in LDRG of diabetic mice. Phosphorylated p38 (pp38 immunoreactivity was detected mostly in the small- to medium-sized LDRG neurons during the time period of mechanical allodynia. Treatment with an antibody against nerve growth factor (NGF significantly inhibited p38 phosphorylation in LDRG of diabetic mice. In addition, we detected higher levels of inflammatory mediators, including cyclooxygenase (COX 2, inducible nitric oxide synthases (iNOS, and tumor necrosis factor (TNF-α in LDRG neurons of db/db mice compared to non-diabetic db+ mice. Intrathecal delivery of SB203580, a p38 inhibitor, significantly inhibited the development of mechanical allodynia and the upregulation of COX2, iNOS and TNF-α. Conclusions Our findings suggest that NGF activated-p38 phosphorylation mediates mechanical allodynia in the db/db mouse by upregulation of multiple inflammatory mediators in LDRG.

  5. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.

    Directory of Open Access Journals (Sweden)

    Sander Barnhoorn

    2014-10-01

    Full Text Available As part of the Nucleotide Excision Repair (NER process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS, or the infantile lethal cerebro-oculo-facio-skeletal (COFS syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.

  6. Protocols for vaginal inoculation and sample collection in the experimental mouse model of Candida vaginitis.

    Science.gov (United States)

    Yano, Junko; Fidel, Paul L

    2011-01-01

    Vulvovaginal candidiasis (VVC), caused by Candida species, is a fungal infection of the lower female genital tract that affects approximately 75% of otherwise healthy women during their reproductive years. Predisposing factors include antibiotic usage, uncontrolled diabetes and disturbance in reproductive hormone levels due to pregnancy, oral contraceptives or hormone replacement therapies. Recurrent VVC (RVVC), defined as three or more episodes per year, affects a separate 5 to 8% of women with no predisposing factors. An experimental mouse model of VVC has been established and used to study the pathogenesis and mucosal host response to Candida. This model has also been employed to test potential antifungal therapies in vivo. The model requires that the animals be maintained in a state of pseudoestrus for optimal Candida colonization/infection. Under such conditions, inoculated animals will have detectable vaginal fungal burden for weeks to months. Past studies show an extremely high parallel between the animal model and human infection relative to immunological and physiological properties. Differences, however, include a lack of Candida as normal vaginal flora and a neutral vaginal pH in the mice. Here, we demonstrate a series of key methods in the mouse vaginitis model that include vaginal inoculation, rapid collection of vaginal specimens, assessment of vaginal fungal burden, and tissue preparations for cellular extraction/isolation. This is followed by representative results for constituents of vaginal lavage fluid, fungal burden, and draining lymph node leukocyte yields. With the use of anesthetics, lavage samples can be collected at multiple time points on the same mice for longitudinal evaluation of infection/colonization. Furthermore, this model requires no immunosuppressive agents to initiate infection, allowing immunological studies under defined host conditions. Finally, the model and each technique introduced here could potentially give rise to use of

  7. Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with KitWv Mutations

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    Ayano Yurino

    2016-09-01

    Full Text Available In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous KitWv mutations into C57BL/6.Rag2nullIl2rgnull mice with NOD-Sirpa (BRGS strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34+CD38− cord blood cells, these newly generated C57BL/6.Rag2nullIl2rgnullNOD-Sirpa KitWv/Wv (BRGSKWv/Wv mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSKWv/Wv mouse model is a useful tool to study human multi-lineage hematopoiesis.

  8. Overview of Genetically Engineered Mouse Models of Breast Cancer Used in Translational Biology and Drug Development.

    Science.gov (United States)

    Greenow, Kirsty R; Smalley, Matthew J

    2015-01-01

    Breast cancer is a heterogeneous condition with no single standard of treatment and no definitive method for determining whether a tumor will respond to therapy. The development of murine models that faithfully mimic specific human breast cancer subtypes is critical for the development of patient-specific treatments. While the artificial nature of traditional in vivo xenograft models used to characterize novel anticancer treatments has limited clinical predictive value, the development of genetically engineered mouse models (GEMMs) makes it possible to study the therapeutic responses in an intact microenvironment. GEMMs have proven to be an experimentally tractable platform for evaluating the efficacy of novel therapeutic combinations and for defining the mechanisms of acquired resistance. Described in this overview are several of the more popular breast cancer GEMMs, including details on their value in elucidating the molecular mechanisms of this disorder.

  9. The transcobalamin receptor knockout mouse: a model for vitamin B12 deficiency in the central nervous system.

    Science.gov (United States)

    Lai, Shao-Chiang; Nakayama, Yasumi; Sequeira, Jeffrey M; Wlodarczyk, Bogdan J; Cabrera, Robert M; Finnell, Richard H; Bottiglieri, Teodoro; Quadros, Edward V

    2013-06-01

    The membrane receptor (TCblR/CD320) for transcobalamin (TC)-bound cobalamin (Cbl) facilitates the cellular uptake of Cbl. A genetically modified mouse model involving ablation of the CD320 gene was generated to study the effects on cobalamin homeostasis. The nonlethal nature of this knockout and the lack of systemic cobalamin deficiency point to other mechanisms for cellular Cbl uptake in the mouse. However, severe cobalamin depletion in the central nervous system (CNS) after birth (Pmouse model; however, it does provide a model with which to evaluate metabolic pathways and genes affected. PMID:23430977

  10. Reducing GABAergic inhibition restores cognitive functions in a mouse model of Down syndrome.

    Science.gov (United States)

    Potier, Marie-Claude; Braudeau, Jérôme; Dauphinot, Luce; Delatour, Benoît

    2014-02-01

    Alterations in excitatory-inhibitory balance occur in Down syndrome and could be responsible for cognitive deficits observed through the life of all individuals carrying an extra copy of chromosome 21. Excess of inhibition in the adult could produce synaptic plasticity deficits that may be a primary mechanism contributing to learning and memory impairments. In this study we discuss pharmacological treatments that could potentially alleviate neuronal inhibition and have been tested in a mouse model of Down syndrome. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system that binds to GABA-benzodiazepine receptors, opens a chloride channel and reduces neuronal excitability. These receptors have been extensively studied as targets for treatment of epilepsy, anxiety, sleep, cognitive disorders and the induction of sedation. Molecules that are either antagonists or inverse agonists of the GABA-benzodiazepine receptors are able to reduce inhibitory GABAergic transmission. However modulating the excitatory-inhibitory balance towards increase of cognition without inducing seizures remains difficult particularly when using GABA antagonists. In this study we review data from the literature obtained using inverse agonists selective for the α5-subunit containing receptor. Such inverse agonists, initially developed as cognitive enhancers for treatment of memory impairments, proved to be very efficient in reversing learning and memory deficits in a Down syndrome mouse model after acute treatment.

  11. Nucleotide excision repair- and p53-deficient mouse models in cancer research

    Energy Technology Data Exchange (ETDEWEB)

    Hoogervorst, Esther M. [Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven (Netherlands); Utrecht University, Department of Pathobiology, Utrecht (Netherlands); Steeg, Harry van [Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven (Netherlands); Vries, Annemieke de [Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven (Netherlands)]. E-mail: Annemieke.de.Vries@rivm.nl

    2005-07-01

    Cancer is caused by the loss of controlled cell growth due to mutational (in)activation of critical genes known to be involved in cell cycle regulation. Three main mechanisms are known to be involved in the prevention of cells from becoming cancerous; DNA repair and cell cycle control, important to remove DNA damage before it will be fixed into mutations and apoptosis, resulting in the elimination of cells containing severe DNA damage. Several human syndromes are known to have (partially) deficiencies in these pathways, and are therefore highly cancer prone. Examples are xeroderma pigmentosum (XP) caused by an inborn defect in the nucleotide excision repair (NER) pathway and the Li-Fraumeni syndrome, which is the result of a germ line mutation in the p53 gene. XP patients develop skin cancer on sun exposed areas at a relatively early age, whereas Li-Fraumeni patients spontaneously develop a wide variety of early onset tumors, including sarcomas, leukemia's and mammary gland carcinomas. Several mouse models have been generated to mimic these human syndromes, providing us information about the role of these particular gene defects in the tumorigenesis process. In this review, spontaneous phenotypes of mice deficient for nucleotide excision repair and/or the p53 gene will be described, together with their responses upon exposure to either chemical carcinogens or radiation. Furthermore, possible applications of these and newly generated mouse models for cancer will be given.

  12. Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease

    Science.gov (United States)

    Noelker, Carmen; Morel, Lydie; Lescot, Thomas; Osterloh, Anke; Alvarez-Fischer, Daniel; Breloer, Minka; Henze, Carmen; Depboylu, Candan; Skrzydelski, Delphine; Michel, Patrick P.; Dodel, Richard C.; Lu, Lixia; Hirsch, Etienne C.; Hunot, Stéphane; Hartmann, Andreas

    2013-01-01

    In mammalians, toll-like receptors (TLR) signal-transduction pathways induce the expression of a variety of immune-response genes, including inflammatory cytokines. It is therefore plausible to assume that TLRs are mediators in glial cells triggering the release of cytokines that ultimately kill DA neurons in the substantia nigra in Parkinson disease (PD). Accordingly, recent data indicate that TLR4 is up-regulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in a mouse model of PD. Here, we wished to evaluate the role of TLR4 in the acute mouse MPTP model of PD: TLR4-deficient mice and wild-type littermates control mice were used for the acute administration way of MPTP or a corresponding volume of saline. We demonstrate that TLR4-deficient mice are less vulnerable to MPTP intoxication than wild-type mice and display a decreased number of Iba1+ and MHC II+ activated microglial cells after MPTP application, suggesting that the TLR4 pathway is involved in experimental PD. PMID:23462811

  13. (18)F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model.

    Science.gov (United States)

    Kao, Hao-Wen; Chen, Chuan-Lin; Chang, Wen-Yi; Chen, Jenn-Tzong; Lin, Wuu-Jyh; Liu, Ren-Shyan; Wang, Hsin-Ell

    2013-02-15

    Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GalH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P ASGPR blocking agent. Animal studies showed the accumulation of (18)F-FBHGal in fibrosis liver (14.84±1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50±1.51 %ID/g, P ASGPR-related liver dysfunction.

  14. Aberrant LncRNA Expression Profile in a Contusion Spinal Cord Injury Mouse Model

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    Ya Ding

    2016-01-01

    Full Text Available Long noncoding RNAs (LncRNAs play a crucial role in cell growth, development, and various diseases related to the central nervous system. However, LncRNA differential expression profiles in spinal cord injury are yet to be reported. In this study, we profiled the expression pattern of LncRNAs using a microarray method in a contusion spinal cord injury (SCI mouse model. Compared with a spinal cord without injury, few changes in LncRNA expression levels were noted 1 day after injury. The differential changes in LncRNA expression peaked 1 week after SCI and subsequently declined until 3 weeks after injury. Quantitative real-time polymerase chain reaction (qRT-PCR was used to validate the reliability of the microarray, demonstrating that the results were reliable. Gene ontology (GO analysis indicated that differentially expressed mRNAs were involved in transport, cell adhesion, ion transport, and metabolic processes, among others. Kyoto Encyclopedia of Genes and Genomes (KEGG enrichment analysis showed that the neuroactive ligand-receptor interaction, the PI3K-Akt signaling pathway, and focal adhesions were potentially implicated in SCI pathology. We constructed a dynamic LncRNA-mRNA network containing 264 LncRNAs and 949 mRNAs to elucidate the interactions between the LncRNAs and mRNAs. Overall, the results from this study indicate for the first time that LncRNAs are differentially expressed in a contusion SCI mouse model.

  15. Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome.

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    Bredford Kerr

    Full Text Available BACKGROUND: Rett syndrome (RTT is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2 and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2(-/y. PRINCIPAL FINDINGS: We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models. CONCLUSIONS/SIGNIFICANCE: We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.

  16. Psidium guajava leaf extract prevents intestinal colonization of Citrobacter rodentium in the mouse model

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    Pooja Gupta

    2015-01-01

    Full Text Available Diarrheal diseases are the second highest cause of mortality of children under 5 years worldwide. There is a continuous search for developing a cost-effective treatment for diarrhea as the present ones are facing challenges. Medicinal plants can be explored further as an alternative treatment for diarrhea. Psidium guajava leaves have been used as an antidiarrheal globally. Citrobacter rodentium, a common mouse pathogen, is known to mimic the pathogenecity of enteropathogenic and enterohemorrhagic E. coli. It can thus present an effective model to study infectious diarrhea. In the present study, the P. guajava leaf extract was tested for its efficacy in treating infectious diarrhea using a C. rodentium mouse model. The mice in the test group (treated with P. guajava leaf extract showed quicker clearance of infection as compared with the control group. The bacterial load in the fecal sample of the mice in the test group was high on Day 4 as compared with that in the control group, suggesting a flush out of the bacteria. In the test group, 6/7 (85.71% mice showed clearance of infection by Day 19. The control group continued to show infection till Day 29. P. guajava leaf extract thus has the potential for use in the treatment of infectious diarrhea.

  17. Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Sahashi, Kentaro; Katsuno, Masahisa; Hung, Gene; Adachi, Hiroaki; Kondo, Naohide; Nakatsuji, Hideaki; Tohnai, Genki; Iida, Madoka; Bennett, C Frank; Sobue, Gen

    2015-11-01

    Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here, we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAG expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target.

  18. Lithium prevents parkinsonian behavioral and striatal phenotypes in an aged parkin mutant transgenic mouse model.

    Science.gov (United States)

    Lieu, Christopher A; Dewey, Colleen M; Chinta, Shankar J; Rane, Anand; Rajagopalan, Subramanian; Batir, Sean; Kim, Yong-Hwan; Andersen, Julie K

    2014-12-01

    Lithium has long been used as a treatment for the psychiatric disease bipolar disorder. However, previous studies suggest that lithium provides neuroprotective effects in neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease. The exact mechanism by which lithium exerts these effects still remains unclear. In the present study, we evaluated the effects of low-dose lithium treatment in an aged mouse model expressing a parkin mutation within dopaminergic neurons. We found that low-dose lithium treatment prevented motor impairment as demonstrated by the open field test, pole test, and rearing behavior. Furthermore, lithium prevented dopaminergic striatal degeneration in parkin animals. We also found that parkin-induced striatal astrogliosis and microglial activation were prevented by lithium treatment. Our results further corroborate the use of this parkin mutant transgenic mouse line as a model for PD for testing novel therapeutics. The findings of the present study also provide further validation that lithium could be re-purposed as a therapy for PD and suggest that anti-inflammatory effects may contribute to its neuroprotective mechanisms. PMID:25452026

  19. The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

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    Maria Gulinello

    2011-01-01

    Full Text Available To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.

  20. Morphokinetic Evaluation of Embryo Development in a Mouse Model: Functional and Molecular Correlates.

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    Weinerman, Rachel; Feng, Rui; Ord, Teri S; Schultz, Richard M; Bartolomei, Marisa S; Coutifaris, Christos; Mainigi, Monica

    2016-04-01

    Although time-lapse analysis of early embryo cleavage parameters (morphokinetics) predicts blastocyst development, it has not been definitively linked to establishing pregnancy and live birth. For example, a direct comparison of the developmental potential of embryos with optimal kinetic parameters compared to suboptimal kinetics has not been performed with human embryos. To ascertain whether such a linkage exists, we developed a mouse model of morphokinetic analysis of early embryo cleavage using time-lapse microscopy to predict blastocyst formation and tested whether cleavage parameters predict pregnancy outcome by transferring morphokinetically optimal and suboptimal embryos into a single host. Using classification and regression trees, we established that the timing of the second and third mitotic divisions (division from two to three and three to four cells, respectively) predicts blastocyst development in the mouse. Using this prediction model, we found that the incidence of sustained implantation at mid-gestation was significantly higher for the optimal compared to suboptimal embryos. In addition, the incidence of resorption among implanted embryos was significantly higher in the suboptimal compared to the optimal group. Transcript profiling of optimal and suboptimal embryos revealed minimal differences between the two groups, suggesting that time-lapse imaging of early embryo cleavage events provides additional information regarding developmental competence apart from gene expression. PMID:26911427