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PubMed2006

An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection.

An animal model for human hepatitis B virus (HBV) tolerance is needed to investigate the mechanisms. This model will also facilitate therapeutic strategies for the existing 350 million patients with chronic hepatitis B. We established a mouse model by hydrodynamic injection of an engineered, replication-competent HBV DNA into the tail veins of C57BL/6 mice. In 40% of the injected mice, HBV surface antigenemia persisted for > 6 months. Viral replication intermediates, transcripts, and proteins were detected in the liver tissues of the injected mice for up to 1 year. The tolerance toward HBV surface antigen in this model was shown to be due to an insufficient cellular immunity against hepatitis B core antigen, as was documented in humans. This animal model will accelerate further genetic and mechanistic studies of human chronic hepatitis B infection.

Animals↗
PubMed2002

Regulation of the Mdr1 isoforms in a p53-deficient mouse model.

Both p53 and multidrug transporters play important roles in chemoresistance. A transcriptional dependence of the Mdr1 gene promoter by p53 was first established a decade ago, and despite intense study, the p53-Mdr1 relationship still remains vague in vivo. The general model proposes that wild-type p53 down regulates, while mutant p53 up regulates, the Mdr1 promoter. Given that many studies have utilized cancer cell lines, minimal promoters and non-specific cDNA expression for in vitro experiments, we first sought to confirm the model using dermal fibroblasts isolated from the p53-knockout mice. We show that the gene products of the mouse Mdr1 homologue (Mdr1a and Mdr1b), namely P-glycoprotein (P-gp), appear upregulated at both the protein and mRNA levels in p53(-/-) mFbs compared with p53(+/+) cells. We demonstrate that transient transfection of a mouse p53(WT) expression plasmid into short-term primary p53(-/-) fibroblasts can revert P-gp overexpression. The difference in P-gp levels has functional significance in that p53(-/-) fibroblasts are more resistant to doxorubicin and vincristine treatment and this resistance can be attenuated in the presence of the P-gp inhibitor, verapamil. Furthermore, we demonstrate that in kidney, spleen and testis, P-gp expression is elevated in the absence of p53. In contrast, other organs such as heart, liver, lung, brain, thymus and skeletal muscle, show no difference in expression between p53(+/+) and p53(-/-) mice. Thus, our data shows a tissue-specific regulation of P-gp isoforms by p53 in the context of a p53-null mouse model.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA.

Construction of animal models of human inherited diseases is particularly important for testing gene therapy approaches. Towards this end, we constructed a mouse model for Charcot-Marie-Tooth disease type 1A by pronuclear injection of a YAC containing the human PMP22 gene. In one transgenic line, the YAC DNA is integrated in about eight copies and the PMP22 gene is strongly expressed to give a peripheral neuropathy closely resembling the human pathology. The disorder is dominant, causes progressive weakness of the hind legs, and there is severe demyelination in the peripheral nervous system including the presence of onion bulb formations. This approach will be valuable for pathologies produced by over-expression of a gene including trisomy and amplification in cancer. Such models will be particularly useful for testing gene therapy approaches if the transgene is human.

Animals↗
PubMed2003

Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.

Animals↗
PubMed2004

Further characterization of the genetic defect of the Bent tail mouse, a mouse model for human neural tube defects.

BACKGROUND: Neural tube defects (NTDs) are congenital malformations arising mostly from incomplete neural tube closure during early embryogenesis. Most NTDs in humans have a complex etiology, with involvement of both genetic and environmental factors. More than 100 mouse models for human neural tube defects exist; Bent tail is one of them. The mouse mutant is caused by a submicroscopic deletion on Xq that completely encompasses the Zic3 gene. METHODS: We searched the ENSEMBL database for other genes/transcribed sequences in the Bent tail deletion in addition to Zic3, which we confirmed by PCR analysis. RESULTS: In our study, we show that the Bent tail deletion is at least 300 kb in size, encompassing a processed pseudogene and a number of expressed sequence tags in addition to Zic3. Although more research is needed to clarify the identity and function of the deleted transcripts, most of them are expressed during embryonic development and might therefore contribute to the phenotype of the Bent tail mouse. CONCLUSIONS: This study presents the first evidence for the fact that the Bent tail allele is not merely a Zic3 knockout allele, as has been previously suggested.

Animals↗
PubMed2006

An orally active, primate selective antagonist of LFA-1 inhibits delayed-type hypersensitivity in a humanized-mouse model.

Compound I, a novel small molecule antagonist (Kd=6 nM) of human lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) was tested for activity in a humanized mouse model of delayed-type hypersensitivity (trans vivo delayed-type hypersensitivity). Trans vivo delayed-type hypersensitivity is a model for testing compounds with human targets in mice. Tetanus toxoid and 7-10x10(6) human peripheral blood mononuclear cells from tetanus-sensitized donors were coinjected into footpads of naive mice. Footpads were measured before and 24 h later. Injection of peripheral blood mononuclear cells plus antigen resulted in swelling of 0.178-0.254 mm, significantly greater than peripheral blood mononuclear cells or tetanus toxoid alone (P<0.05). Preincubation of peripheral blood mononuclear cells with anti-human major histocompatibility complex class II (MHCII) or anti-human LFA-1 monoclonal antibody (mAb), but not anti-mouse MHCII or anti-mouse LFA-1 mAb, significantly inhibited the response. Compound I inhibited footpad swelling in a dose related manner (0.1-100 mg/kg, p.o.; ED50 approximately 1 mg/kg), whereas its enantiomer had no effect. These data demonstrate the oral efficacy of a novel antagonist of LFA-1 in trans vivo delayed-type hypersensitivity.

Administration, Oral↗
PubMed2003

The SCID mouse model: novel therapeutic targets - lessons from gene transfer.

The hallmark of rheumatoid arthritis (RA) is progressive destruction of the joints, preceded and accompanied by synovial hyperplasia and chronic inflammation. Spontaneous and induced animal models of RA reflect predominantly the inflammatory aspects of the disease. To reproduce the destruction of cartilage and bone mediated by an activated synovium, it was desirable to develop models that allow the dissection of cellular and molecular components derived from human tissue. The SCID mouse co-implantation model of human RA focuses on RA synovial fibroblasts (RA-SF) and their role in cartilage destruction. The model has provided the best evidence that RA-SF contribute significantly to matrix degradation, even in the absence of human lymphocytes and macrophages, since highly purified RA-SF invade the co-implanted normal human cartilage. Moreover, it became clear that they maintained their aggressive phenotype over long periods of time, particularly at sites of invasion into the co-implanted human cartilage. Targeting different signaling molecules, cytokines and matrix-degrading enzymes by soluble receptors, antagonists or negative mutants in the SCID mouse model of RA has implicated many of them in the mechanisms leading to cartilage destruction. However, since inhibition of a single molecule or pathway is not sufficient to inhibit the aggressive behavior of RA-SF it appears necessary to co-express in the synoviocytes genes for two or even more antagonists of e.g. cytokines, matrix-degrading enzymes or molecules interfering specifically with signaling pathways involved in the apoptosis of RA-SF. Based on the recent observation that the L1 (line-1) endogenous retroviral element appears responsible for the cytokine- independent activation via the MAPK p38delta, the current understanding of disease pathogenesis suggests that both the cytokine-dependent as well as the cytokine-independent pathways of joint destruction must be inhibited. Modulation of both pathways by gene transfer approaches in the SCID mouse model is a feasible method aimed at identifying novel targets for the prevention of cartilage destruction in RA.

Animals↗
PubMed1994

A mouse model for studies of mucosal immunity to vaginal infection by herpes simplex virus type 2.

BACKGROUND: The role of mucosal immunity in defense of the female genital tract against pathogens such as herpes simplex virus-2 (HSV-2) is poorly understood. Here we explored the use of a new mouse model to determine whether local immune events in the vagina of immune animals may protect them against genital herpes. EXPERIMENTAL DESIGN: The effect of the estrous cycle, pregnancy, and sex hormones on vaginal infection of adult mice by HSV-2 was determined by immunolabeling of virus proteins. The immune response to infection was studied by immunolabeling of T lymphocytes, B lymphocytes, and plasma cells in the vagina of infected mice. RESULTS: Inoculation of attenuated virus (TK-HSV-2) or wild-type virus (TK+HSV-2) into the vagina on day 6 of pregnancy or after treatment with Depo-Provera (DP) caused infection of the vaginal epithelium. In contrast, these viruses did not cause infection after vaginal inoculation at estrus, metestrus, or after treatment with Depo-Estradiol. Infected mice showed immunolabeling of virus in the vaginal epithelium from 24 hrs to 5 days after virus inoculation. The immune response to infection included upregulation of class II MHC antigen in vaginal epithelium, CD8+ T cells in epithelium and stroma, and plasma cells and lymphoid nodules in the stroma. Mice that were infected with TK-HSV-2 did not exhibit infection of vaginal epithelium when challenged 6 weeks later with TK+HSV-2. CONCLUSIONS: Progesterone-dominated adult mice become infected after intravaginal inoculation with HSV-2, but estradiol-dominated mice are refractory. Vaginal infection with attenuated HSV-2 produces immunity that protects mice against later infection by wild-type virus. This immunity either prevents infection of vaginal epithelium or severely inhibits viral replication in the epithelium. The observations suggest that the E/DP-treated adult mouse should be a useful model for studies of mucosal immunity to vaginal infection by HSV-2.

Animals↗
PubMed2006

NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease.

Alzheimer's disease is characterized by two primary pathological features: amyloid plaques and neurofibrillary tangles. The interconnection between amyloid and tau aggregates is of intense interest, but mouse models have yet to reveal a direct interrelationship. We now show that NO may be a key factor that connects amyloid and tau pathologies. Genetic removal of NO synthase 2 in mice expressing mutated amyloid precursor protein results in pathological hyperphosphorylation of mouse tau, its redistribution to the somatodendritic compartment in cortical and hippocampal neurons, and aggregate formation. Lack of NO synthase 2 in the amyloid precursor protein Swedish mutant mouse increased insoluble beta-amyloid peptide levels, neuronal degeneration, caspase-3 activation, and tau cleavage, suggesting that NO acts at a junction point between beta-amyloid peptides, caspase activation, and tau aggregation.

Alzheimer Disease↗
PubMed2006

Metformin therapy in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disease that leads to striatal degeneration and a severe movement disorder. We used a transgenic mouse model of HD (the R6/2 line with approximately 150 glutamine repeats) to test a new therapy for this disease. We treated HD mice with metformin, a widely used anti-diabetes drug, in the drinking water (0, 2 or 5mg/ml) starting at 5 weeks of age. Metformin treatment significantly prolonged the survival time of male HD mice at the 2mg/ml dose (20.1% increase in lifespan) without affecting fasting blood glucose levels. This dose of metformin also decreased hind limb clasping time in 11-week-old mice. The higher dose did not prolong survival, and neither dose of metformin was effective in female HD mice. Collectively, our results suggest that metformin may be worth further investigation in additional HD models.

AMP-Activated Protein Kinases↗
PubMed1997

Transgenic mouse models for studying mutations in vivo: applications in aging research.

To study mutation accumulation in the DNA of somatic cells and tissues during aging in vivo, a transgenic mouse model has been constructed. The model harbors plasmid vectors, containing the lacZ reporter gene, integrated head to tail at various chromosomal locations. Procedures have been worked out to efficiently recover the plasmids into E. coli host cells. A positive selection system, permitting only E. coli cells with a lacZ mutated plasmid to grow, allows for the accurate determination of mutation frequencies as the ratio of mutant colonies versus the total number of transformants, i.e., the total number of plasmid copies recovered. Results obtained from a life span study of plasmid mice with vector clusters on chromosome 3 and 4 indicated age-related mutation accumulation in the liver, but not in the brain. Comparison of the mutational spectra revealed a significantly larger proportion of large size-change mutations in liver than in brain.

Aging↗
PubMed1997

Transgenic mouse models for studying mutations in vivo: applications in aging research.

To study mutation accumulation in the DNA of somatic cells and tissues during aging in vivo, a transgenic mouse model has been constructed. The model harbors plasmid vectors, containing the lacZ reporter gene, integrated head to tail at various chromosomal locations. Procedures have been worked out to efficiently recovery the plasmids into E. coli host cells. A positive selection system, permitting only E. coli cells with a lacZ mutated plasmid to grow, allows for the accurate determination of mutation frequencies as the ratio of mutant colonies versus the total number of transformants, i.e., the total number of plasmid copies recovered. Results obtained from a life span study of plasmid mice with vector clusters on chromosome 3 and 4 indicated age-related mutation accumulation in the liver, but not in the brain. Comparison of the mutational spectra revealed a significantly larger proportion of large size-change mutations in liver than in brain.

Aging↗
PubMed2002

Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain.

The Mecp2 gene has been shown to be mutated in most cases of human Rett syndrome, and mouse models deleted for the ortholog have been generated. Lineage-specific deletion of the gene indicated that the Rett-like phenotype is caused by Mecp2 deficiency in neurons. Biochemical evidence suggests that Mecp2 acts as a global transcriptional repressor, predicting that mutant mice should have genome-wide transcriptional deregulation. We tested this hypothesis by comparing global gene expression in wild-type and Mecp2 mutant mice. The results of numerous microarray analyses revealed no dramatic changes in transcription even in mice displaying overt disease symptoms, although statistical power analyses of the data indicated that even a small number of relatively subtle changes in transcription would have been detected if present. However, a classifier consisting of a combined small set of genes was able to distinguish between mutant and wild-type samples with high accuracy. This result suggests that Mecp2 deficiency leads to subtle gene expression changes in mutant brains which may be associated with the phenotypic changes observed.

Age Factors↗
PubMed2005

Aerosolized hyaluronan limits airspace enlargement in a mouse model of cigarette smoke-induced pulmonary emphysema.

This study was designed to determine if aerosolized hyaluronan (HA) could prevent airspace enlargement and elastic fiber injury in a mouse model of cigarette smoke-induced pulmonary emphysema. Compared to untreated/smoked controls, HA-treated animals showed statistically significant reductions in mean linear intercept (54 versus 65 microm; P < .001) and elastic fiber breakdown products (desmosine and isodesmosine) in bronchoalveolar lavage fluid (0.3 versus 7.0 ng/mL; P < .05). As in previous studies, the aerosolized HA showed preferential binding to elastic fibers, suggesting that it may protect them from injury. These findings support further investigation of the potential use of HA as a treatment for pulmonary emphysema.

Adjuvants, Immunologic↗
PubMed1999

The topical microbicide PRO 2000 protects against genital herpes infection in a mouse model.

Vaginal gel formulations containing the naphthalene sulfonate polymer PRO 2000 are being developed as topical microbicides to protect against infection with sexually transmitted disease (STD) pathogens. A mouse model was used to determine whether PRO 2000 could protect against genital herpes in vivo. Animals received a single intravaginal application of 15 microL of a 10% PRO 2000 aqueous solution or a 4.0% or 0.5% PRO 2000 vaginal gel formulation 20 s prior to intravaginal challenge with 4.0 log10 pfu of herpes simplex virus type 2. Treatment with the 4.0% gel provided complete protection against infection; treatment with the 0.5% gel or 10% solution provided 81% and 80% protection, respectively. Furthermore, the 4% gel provided significant protection even when viral challenge was delayed until 60 min after treatment. This is the first report to show that PRO 2000 can protect against infection with an STD pathogen in vivo.

Administration, Topical↗
PubMed2000

Efficacy of a novel tetracycline derivative, glycylcycline, against penicillin-resistant Streptococcus pneumoniae in a mouse model of pneumonia.

The MIC90 of glycylcycline (< or =0.06 mg/L) against 55 strains of Streptococcus pneumoniae was 100-fold lower than that of minocycline or tetracycline. In a mouse model of penicillin-resistant S. pneumoniae (PRSP) pneumonia, glycylcycline (10 mg/kg) decreased bacterial counts in the lungs from 10(6) cfu to <10(2) cfu, whereas no apparent reduction of bacterial numbers was observed with minocycline or penicillin G. Pharmacokinetic studies showed that the half-life and area under the curve of glycylcycline were superior to those of minocycline and penicillin G in the lungs. These results show a preferential distribution of glycylcycline in the lungs and potent in vivo bactericidal activity in PRSP pneumonia.

Animals↗
PubMed1999

Role of autoreactive CD8+ T cells in organ-specific autoimmune diseases: insight from transgenic mouse models.

There is now convincing evidence that autoreactive CD8+ T cells can contribute to the pathogenesis of organ-specific autoimmune diseases. In the non-obese diabetic mouse, there is direct evidence that beta-islet cell-specific CD8+ cytotoxic T cells have a pathogenic effect. In human diseases such as autoimmune diabetes and multiple sclerosis, indirect evidence also suggests a role for CD8+ T cells in tissue damage, although their antigen specificity is unknown. Transgenic mouse models as well as the use of knockout mice have been instrumental in the identification of the role of autoreactive CD8+ T cells. Spontaneous models of CD8+ T-cell-mediated autoimmunity generated through transgenesis should help delineate the effector mechanisms leading to tissue destruction. The study of autoreactive CD8+ T cells and the characterization of their antigenic specificity should help unravel the pathophysiology of organ-specific autoimmune diseases, help identify exacerbating foreign antigens, and allow the design of antigen-specific immunotherapy targeting the pathogenic autoreactive T cells.

Animals↗
PubMed2004

Effect of amoxicillin-clavulanic acid on human fecal flora in a gnotobiotic mouse model assessed with fluorescence hybridization using group-specific 16S rRNA probes in combination with flow cytometry.

Predominant groups of bacteria from a human fecal flora-associated mouse model challenged with amoxicillin-clavulanic acid were quantified with fluorescence in situ hybridization combined with flow cytometry using specific 16S rRNA targeted oligonucleotide probes. This approach provides a useful tool with high throughput to evaluate fecal microflora under antibiotic treatment.

Amoxicillin-Potassium Clavulanate Combination↗