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PubMed2006

Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi-allogeneic mouse model.

BACKGROUND: A mouse uterus transplantation model has previously been developed for studies of various aspects of uterine transplantation, which in the future may be used as treatment for uterine infertility. The aim of the study was to evaluate the effect of the immunosuppressant cyclosporine A (CyA) on the rejection of the allotransplanted uterus in the mouse. METHODS: C57BL/6 mice were recipients of uteri from F1 hybrids (C57BL/6 x CBA/ca). Transplanted mice received vehicle (control, n=5), 10 or 20 mg/kg/day of CyA (CyA10, n=5 and CyA20, n=5). Untreated F1 hybrids with syngeneic transplants (n=3) were negative controls. On day 10 post-transplantation, the grafted uteri were examined, and biopsies were taken for histology and quantification of T cells. RESULTS: Histology analysis revealed necrosis of the uterine transplants in controls and to a lesser extent in the CyA groups. Apoptosis and inflammation was prominent in grafts from the CyA10 group but suppressed in the CyA20 group. A similar increase of CD4+ cells was seen in all groups, whereas the number of CD8+ cells was higher (P < 0.05) in the two allogeneic groups receiving CyA compared with the allogeneic vehicle group. CONCLUSIONS: CyA treatment clearly delays the progress of rejection of grafted uteri but is insufficient to suppress T cell infiltration. Interestingly, the number of CD8+ cells was higher in groups receiving CyA, possibly reflecting a CyA-dependent depression of activation-induced cell death (AICD) of cytotoxic T cells.

Animals↗
PubMed2002

New mouse model of vein bypass graft atherosclerosis.

Animal models of vein graft disease are used as preliminary tools to study and understand the pathogenesis of the disease in humans and improve its diagnosis, prevention and therapy. Several animal models that manifest lesions resembling neointimal hyperplasia of human vein grafts have been developed, but there are limitations in studying the mechanism of this disease in these models. We previously established a mouse model of vein bypass graft atherosclerosis that allows us to take advantage of transgenic and knockout techniques. Using this model, we studied the pathogenesis of vein graft atherosclerosis. The lesion in the grafts was characterised by mononuclear cell infiltration followed by smooth muscle cell (SMC) proliferation and matrix protein deposition, which is similar to the human lesion. Studies of the molecular mechanism of pathogenesis in this model revealed that physical force initiated signal pathways, particularly mitogen-activated protein kinases (MAPK), leading to vascular cell death and an inflammatory response, followed by SMC proliferation, which contributed to the development of arteriosclerosis. Suramin inhibited SMC migration and proliferation in vivo and in vitro by blocking platelet-derived growth factor (PDGF)-initiated PDGF receptor activation and MAPK-AP-1 signalling, and was also effective in inhibition of neointima hyperplasia in mouse vein bypass grafts. This new mouse model of vein bypass graft atherosclerosis affords us with a valuable new approach to attain further understanding of the mechanism of vein graft disease with the use of transgenic mice, and in evaluating the effects of drugs and gene therapy on vascular diseases.

Journal Article↗
PubMed2003

Insights into the molecular basis of polyglutamine neurodegeneration from studies of a spinocerebellar ataxia type 7 mouse model.

Spinocerebellar ataxia type 7 (SCA7) is one member of a growing list of neurodegenerative disorders that are all caused by CAG repeat expansions that produce disease by encoding elongated polyglutamine tracts in a variety of apparently unrelated proteins. In this review, we provide an overview of our efforts to determine the molecular basis of polyglutamine neurotoxicity in SCA7 by modeling this polyglutamine repeat disorder in mice. We discuss how our SCA7 mouse model develops a phenotype that is reminiscent of the retinal and cerebellar disease pathology seen in human patients. All of these findings are considered in the context of numerous other models of polyglutamine disease pathology in mice and other organisms, together with various other in vitro and biochemical studies. We present the competing hypotheses of polyglutamine disease pathogenesis, and explain how our studies of SCA7 brainstem and retinal degeneration using this mouse model have yielded insights into possible mechanisms and pathways of polyglutamine disease pathology. In addition to illustrating how our SCA7 mouse model has allowed us to develop and advance notions of disease pathogenesis, we propose a model of polyglutamine molecular pathology that attempts to integrate the key observations in the field. We close by describing why our SCA7 mouse model should be useful for the next phase of polyglutamine disease research--the development of therapies, and predict that this stage of experimentation will continue to rely heavily on the mouse.

Ataxin-7↗
PubMed2005

[Growth-inhibiting and anti-metastasis effects of Weichang'an Decoction on orthotopic transplant nude mouse model of human gastric cancer].

OBJECTIVE: To evaluate the growth-inhibiting and anti-metastasis effects of Weichang'an Decoction (WCAD) on orthotopic transplant nude mouse model of human gastric cancer. METHODS: Forty-one nude mice were implanted with SGC-7901 cells at orthotopic site, whereas 25 were implanted with SGC-7901 cells subcutaneously. Then the nude mice in each transplantation model were divided into the same three groups which were WCAD-treated group with WCAD 0.5 ml/d taken orally, 5-FU-treated group with 5-FU 50 mg/kg intraperitoneally injected weekly and untreated control group with physiological saline 0.5 ml/d taken orally. The growth-inhibiting rates of transplant tumors were detected and the metastatic lesions were examined in the orthotopic transplant mouse model while PCNA-positive rate and apoptotic index (AI) were observed in the subcutaneous transplant mouse model. RESULTS: The growth-inhibiting rates in the WCAD-treated and 5-FU-treated groups of orthotopic transplant mouse model were 40.82% and 37.92% respectively whereas those of subcutaneous transplant mouse model were 48.70% and 60.10%. The incidence rates of metastasis in perigastric lymph notes, lymph nodes in the porta hepatis, liver, diaphragm and peritoneum in the WCAD-treated and 5-FU-treated groups were lower than those in the untreated control group, and the total metastasis rates in the WCAD-treated, 5-FU-treated and the untreated control groups were 30.77%, 28.57% and 71.43% respectively with significant differences (P<0.05). The total PCNA-positive rates in the WCAD-treated and 5-FU-treated groups were obviously lower than that in the untreated control group (P<0.05 or P<0.01) while the AI was higher than that in the untreated control group (P<0.01). The growth-inhibiting rate, total PCNA-positive rate and total metastasis rate in the WCAD-treated group had no significant differences as compared with those in the 5-FU-treated group, but the AI in the WCAD-treated group was significantly higher than that in the 5-FU-treated group (P<0.05). CONCLUSION: WCAD has the inhibiting effects on tumor growth and metastasis of gastric cancer which is orthotopic implanted onto nude mice. This effect may be obtained by proliferation suppression and apoptosis induction in cancer.

Animals↗
PubMed2004

Heparin-induced thrombocytopenia and other immune thrombocytopenias: lessons from mouse models.

The prototype immune thrombocytopenia is (auto)immune thrombocytopenic purpura, ITP. The major issues in the pathophysiology, diagnosis, and therapy of ITP are presented. Mouse models of the pathophysiology of ITP have allowed greater understanding of the role of antiplatelet antibodies and of antibody effector mechanisms. In addition, there has been a substantial increase in interest in the use of mouse models to understand the mechanisms of action of therapeutics for ITP, with notable progress for intravenous immunoglobulin (IVIG) and anti-red blood cell therapies. The immune-mediated thrombocytopenia and thrombosis syndromes are a common cause of morbidity and mortality; the prototype is heparin-induced thrombocytopenia and thrombosis (HITT). There has been substantial progress in understanding the pathophysiology, diagnosis, and therapy of HITT in the last decade, but there remain major questions. The four necessary and sufficient elements for HITT in vivo were established in our mouse model (namely platelet factor 4 [PF4], heparin, antibody to the heparin/PF4 complex, and platelet Fc receptor for immunoglobulin G [FcgammaRIIa]). Currently, our HITT mouse models are being used to address a number of questions. For example, what are the roles of antibody titer, isotype, and epitope targets? Are there genetic determinants of platelet activation, such as the platelet FcgammaRIIa receptor density, operable in HITT? What are the roles of tissue factor/factor VIIa (TF/VIIa), monocytes, and blood cell-derived microparticles? What is the contribution of pre-existing endothelial cell (EC) dysfunction, and/or induced EC dysfunction? As in many human disorders, preclinical mouse models will continue to be important in the immune thrombocytopenia syndromes to achieve translation into improved patient care.

Animals↗
PubMed2006

Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1.

Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid-beta (Abeta) accumulation and related cognitive impairments. Although deficits in hippocampus-dependent place learning have been well characterized in Alzheimer's transgenic mice, little is known about temporal memory function in these AD models. Here, we applied trace fear conditioning to two different Alzheimer's mouse models and investigated the relationship between pathogenic Abeta and temporal memory deficits. This behavioral test requires hippocampus-dependent temporal memory processing as the conditioned and unconditioned stimuli are separated by a trace interval of 30 s. We found that both amyloid precursor protein (APP) transgenic (Tg2576) and APP/presenilin (PS)1 transgenic (Tg6799) mice were impaired in memorizing this association across the time gap. Both transgenic groups performed as well as wild-type control mice in delay fear conditioning when the trace interval was removed, indicating that the trace conditioning deficits are hippocampus-specific. Importantly, Tg6799 mice engineered to lack the major Alzheimer's beta-secretase (beta-site APP-cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Abeta oligomers found in Tg6799+ mouse brains returned to wild-type control levels without changes in APP/PS1 transgene expression in BACE1-/- * Tg6799+ bigenic mouse brains, suggesting Abeta oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Abeta-dependent deficits in temporal associative memory. Our gene-based approach suggests that lowering soluble Abeta oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.

Alzheimer Disease↗
PubMed2004

A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program.

Mutant mouse models are indispensable tools for clarifying the functions of genes and for elucidating the underlying pathogenic mechanisms of human diseases. Currently, several large-scale mutagenesis projects that employ the chemical mutagen N-ethyl-N-nitrosourea (ENU) are underway worldwide. One specific aim of our ENU mutagenesis project is to generate diabetic mouse models. We screened 9375 animals for dominant traits using a clinical biochemical test and thereby identified 11 mutations in the glucokinase (Gk) gene that were associated with hyperglycemia. GK is a key regulator of insulin secretion in the pancreatic beta-cell. Approximately 190 heterozygous mutations in the human GK gene have been reported to cause maturity onset diabetes of the young, type 2 (MODY2). In addition, five mutations have been reported to cause permanent neonatal diabetes mellitus (PNDM) when present on both alleles. The mutations in our 11 hyperglycemic mutants are located at different positions in Gk. Four have also been found in human MODY2 patients, and another mutant bears its mutation at the same location that is mutated in a PNDM patient. Thus, ENU mutagenesis is effective for developing mouse models for various human genetic diseases, including diabetes mellitus. Some of our Gk mutant lines displayed impaired glucose-responsive insulin secretion and the mutations had different effects on Gk mRNA levels and/or the stability of the GK protein. This collection of Gk mutants will be valuable for understanding GK gene function, for dissecting the function of the enzyme and as models of human MODY2 and PNDM.

Amino Acid Sequence↗
PubMed2004

Mouse models for studying orthopoxvirus respiratory infections.

Concern regarding the use of variola and monkeypox viruses as bioterrorist agents has led to an increased study of orthopoxviruses to understand the molecular and cellular basis of pathogenesis and develop safe and effective antivirals and vaccines against smallpox. Crucial to these efforts is the availability of animal models, which are inexpensive, genetically homogeneous, and recapitulate the human disease. The popular small-animal orthopoxvirus models employ the inbred mouse as the host, the respiratory tract as the site of virus inoculation, and orthopoxviruses-vaccinia, cowpox, and ectromelia viruses-as surrogates for variola virus. Ectromelia virus is likely the best surrogate for variola virus in a mouse model, as it is infectious at very low doses of virus, and the mousepox disease is associated with high mortality in the susceptible A, BALB/c, and DBA/2 stains of mice, but causes an unapparent infection in the C57BL/6 mouse strain. This chapter describes an ectromelia virus respiratory infection model in the mouse.

Animals↗
PubMed2005

Survey of genetically engineered mouse models for prostate cancer: analyzing the molecular basis of prostate cancer development, progression, and metastasis.

Genetically engineered mouse models have been generated to study the molecular basis of prostate cancer (PCa) development, progression, and metastasis. Selection of a prostate-specific promoter, such as the probasin (PB) and prostate specific antigen (PSA) promoters, is critical for generating sufficient levels of transgene expression to elicit a phenotypic response. To date, target genes have included growth factors, cell cycle regulators, pro- and anti-apoptotic proteins, steroid hormone and growth factor receptors, oncogenes, tumor suppressors, and homeobox genes. The experimental approaches used to generate these mouse models include overexpression of the transgene, knock-out/knock-in of transgene expression and conditional regulation of expression using Cre/lox technology. This review summarizes the promoters, which have been utilized to create genetically engineered mouse models for PCa. Furthermore, the effects of gene disruption on promoting low- and high-grade intraepithelial neoplasia (LGPIN and HGPIN, respectively), locally invasive carcinoma and metastatic lesions will be discussed. To date, the PB-Cre4 x PTENloxp/loxp model appears to be the only model that represents the entire continuum of prostate adenocarcinoma development, tumor progression, and metastasis, although models that develop prostatic neuroendocrine (NE) cancer can be generated by disrupting one genetic event. Indeed, analysis of bigenic mouse models indicates that two genetic events are generally required for progression from HGPIN to locally invasive adenocarcinoma and that two to five genetic events can promote metastasis to distant sites. Studying the effects of genetic perturbation on PCa biology will increase our understanding of the disease process and potentially provide targets for developing novel therapeutic approaches.

Adenocarcinoma↗
PubMed1985

An investigation of a mouse model to estimate the potency of the diphtheria component in vaccines.

A mouse model to estimate the potency of the diphtheria toxoid components in vaccines using Vero cells to detect the neutralizing antibodies in the sera from immunized mice is described. The results obtained with this mouse model correlated significantly with those obtained in the lethal challenge test in guinea-pigs. For this reason it is suggested that the potency test in guinea-pigs be replaced by this mouse model because a considerable reduction in the number of animals used and costs can be achieved by the introduction of this mouse test for the routine control of the potency of the diphtheria component of vaccines.

Animals↗
PubMed1996

Mouse models of human genetic disease: which mouse is more like a man?

There has always been great interest in animal models of human genetic disease, and mice provide the largest number of examples. A mutation in the homologous gene in mice does not always lead to the same phenotype as is found in man, however. Recent studies made it apparent that one mutation can have markedly different phenotypes when placed on different genetic backgrounds. This variation is due to different alleles at modifying loci in various inbred strains. Thus, if one wishes to obtain the optimal mouse model for a human disease, one needs to choose the correct genetic background as well as the correct mutation.

Alleles↗
PubMed2007

Mouse models of acute promyelocytic leukemia.

Mouse models of acute promyelocytic leukemia have been generated through transgenic, knock-in, retroviral, and xenograft strategies. These models have been used to elucidate mechanisms underlying leukemogenesis. Among the areas investigated are the role of reciprocal fusions; effects of target cells, expression levels, and mouse strains; cooperating events; and restrictive and permissive factors. These models have also been used to gain insight into the effects of the immune system on leukemic cells and the mechanism of response to retinoic acid. Furthermore, preclinical studies utilizing these mice have advanced therapy for myeloid leukemia.

Animals↗
PubMed2000

Gastric mucosa-associated lymphoid tissue lymphoma: implications of animal models on pathogenic and therapeutic considerations--mouse models of gastric lymphoma.

There are a number of Helicobacter species that will readily colonise the mouse stomach for the duration of the animal's life. They are Helicobacter felis, "Helicobacter heilmannii" and Helicobacter pylori. Early studies on long-term infection of BALB/c mice showed the presence of lesions resembling low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Because of the suggestion that H. pylori was the cause of these tumors in humans, this phenomenon was studied further as it was reasoned that the Helicobacter-infected mice would provide a valuable model of the human disease. Low-grade gastric MALT lymphomas have been shown to follow infection with all the Helicobacter species listed above. These lesions are indistinguishable from the human disease with the presence of centrocyte-like cells, characteristic lymphoepithelial lesions and glandular destruction. Treatment with antimicrobial therapy results in regression of the lymphomas. There is evidence of progression to high-grade in some animals. The Helicobacter mouse models of lymphoma are likely to provide important information relevant not just to H. pylori-induced lesions in the human, but to antigen-driven tumors in general.

Animals↗
PubMed2006

N-ethyl-N-nitrosourea-based generation of mouse models for mutant G protein-coupled receptors.

Chemical random mutagenesis techniques with the germ line supermutagen N-ethyl-N-nitrosourea (ENU) have been established to provide comprehensive collections of mouse models, which were then mined and analyzed in phenotype-driven studies. Here, we applied ENU mutagenesis in a high-throughput fashion for a gene-driven identification of new mutations. Selected members of the large superfamily of G protein-coupled receptors (GPCR), melanocortin type 3 (Mc3r) and type 4 (Mc4r) receptors, and the orphan chemoattractant receptor GPR33, were used as model targets to prove the feasibility of this approach. Parallel archives of DNA and sperm from mice mutagenized with ENU were screened for mutations in these GPCR, and in vitro assays served as a preselection step before in vitro fertilization was performed to generate the appropriate mouse model. For example, mouse models for inherited obesity were established by selecting fully or partially inactivating mutations in Mc4r. Our technology described herein has the potential to provide mouse models for a GPCR dysfunction of choice within <4 mo and can be extended to other gene classes of interest.

Alkylating Agents↗
PubMedDate not supplied

Pathophysiology of a sickle cell trait mouse model: human alpha(beta)(S) transgenes with one mouse beta-globin allele.

As a potential model for sickle cell trait (AS), we examined mice containing one normal mouse beta-globin allele in combination with a human hemoglobin S (h(alpha)beta(S)) transgene (m(beta)/hS). The mice segregated into two subpopulations containing low and high proportions of hemoglobin S (m(beta)/hS1 and m(beta)/hS2, respectively) that was associated with one or two human h(alpha)beta(S) transgenes. We noted striking kidney pathology (cortical cysts, hyperplastic tubules, and glomerulonephritis), increasing with age and with greater severity in m(beta)/hS1. mBeta/hS2 animals were largely tolerant to 5% O(2) for 1 h, whereas 80% of m(beta)/hS1 mice died, exhibiting acute sequestration of erythrocytes in spleen, liver, and heart. These pathologies appear to result from a decreased oxygen affinity of the hybrid (human alpha/mouse beta) hemoglobins with a mild beta-thalassemia phenotype. Thus, these mouse models of sickle trait seem to manifest their renal pathology and sensitivity to hypoxia by mechanisms related to low tissue oxygen delivery and are different from the human syndrome. Analyses of parameters such as P(50), red cell indices, and genetic background are necessary in establishing potential relevance of any mouse model of the sickle cell syndromes.

Alleles↗
PubMed1999

Lessons learned from the mouse model of short-chain acyl-CoA dehydrogenase deficiency.

The SCAD deficient mouse model has been useful to investigate mechanisms of deficient fatty acid oxidation disease in human patients. This mouse model has been thoroughly characterized and is readily available from the Jackson Laboratory. Using the new technologies of gene-knockout mouse modeling, we envisage developing additional members of the acyl-CoA dehydrogenase family of enzyme deficiencies in mice and furthering our understanding of fatty acid metabolism in health and disease.

Acyl-CoA Dehydrogenase↗
PubMed2002

A novel mouse model of diisocyanate-induced asthma showing allergic-type inflammation in the lung after inhaled antigen challenge.

BACKGROUND: Exposure to diisocyanates, a group of highly reactive, low-molecular-weight compounds, is a major cause of occupational asthma. In contrast to mouse models of atopic asthma, previous mouse models of diisocyanate-induced asthma have failed to show lung inflammation with characteristics of human disease. OBJECTIVE: Our goal was to establish a novel mouse model of diisocyanate-induced asthma in which lung inflammation reminiscent of that seen in human asthma is generated after inhaled antigen challenge. METHODS: BALB/c mice were epicutaneously sensitized to hexamethylene diisocyanate (HDI) and then challenged with an HDI-protein conjugate administered by means of an intranasal droplet. RESULTS: HDI sensitization resulted in development of contact hypersensitivity and HDI-specific antibody production. Most importantly, however, vigorous inflammatory responses with characteristics of human asthma were generated in the lung after inhaled HDI challenge. Challenge of sensitized, but not unsensitized, mice resulted in airway eosinophilia, mucus hypersecretion, and production of T(H)1-type (IFN-gamma) and T(H)2-type (IL-4, IL-5, and IL-13) cytokines by lung inflammatory cells. Despite the mixed T(H)1/T(H)2 response induced by HDI sensitization, use of cytokine-deficient mice revealed that airway eosinophilia was mediated by T(H)2 cytokines and not by IFN-gamma. CONCLUSION: We report a novel mouse model of diisocyanate-induced asthma that, in contrast to previous models, demonstrates antigen-induced lung inflammation with characteristics of human disease. This model will allow investigation of the immunopathogenesis of diisocyanate-induced asthma and should provide insight into this common form of occupational disease.

Administration, Inhalation↗
PubMed1992

Micromanipulation of cleaved embryos cultured in protein-free medium: a mouse model for assisted hatching.

A mouse model for studying anomalies of human embryonic hatching following micromanipulation is proposed. Initiation and completion of mouse blastocyst hatching was severely impaired (34/292; 12% and 28/292; 10%, respectively) with protein deprivation, resembling the situation in human in vitro fertilization. Hatching ability was restored when an artificial gap was introduced in the zona pellucida by micromanipulation at the cleaved embryo stage. This enabled 77% (285/371) and 36% (134/371) of the embryos to initiate and complete hatching in protein-free medium. No differences were found in overall cell counts between the two groups of embryos. Transfer of micromanipulated blastocysts to pseudopregnant females resulted in development of healthy fetuses.

Animals↗