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PubMed1998

Induction of somatic intrachromosomal recombination inversion events by cyclophosphamide in a transgenic mouse model.

Somatic intrachromosomal recombination (SICR) can result in chromosomal inversion and deletion, mechanisms which are important in carcinogenesis. We have utilised a transgenic mouse model to study SICR inversion events in spleen cells. The transgenic construct is designed so that expression of an Escherichia coli lacZ transgene only occurs in a cell when an SICR inversion event occurs in the region of the transgene. The inversion events can then be detected by histochemical staining of frozen spleen sections for transgene expression and by polymerase chain reaction across the inversion breakpoints. The spontaneous inversion frequency in spleen rose 2-fold from 1.54 +/- 0.24 x 10(-4) (mean +/- SE) in 4-month-old transgenic mice to 3.12 +/- 0.67 x 10(-4) in 22-month-old mice. Four- or 8-month-old mice were treated with a single intraperitoneal injection of cyclophosphamide, with doses ranging from 0.01 to 100 mg/kg. The animals were killed 3 days after treatment. A significant induction of SICR inversions was detected at all doses with a 3.2-fold maximum induction of inversions detected at 10 mg/kg. These results suggest that the transgenic mouse model used here may be a sensitive model for studying the role of SICR in mutation and in studying risk assessment of environmental DNA-damaging agents.

Animals↗
PubMed2003

Animal models of melanoma: an HGF/SF transgenic mouse model may facilitate experimental access to UV initiating events.

Cutaneous malignant melanoma, the most lethal of the skin cancers, known for its intractability to current therapies, continues to increase in incidence, providing a significant public health challenge. There is a consensus that skin cancer is initiated by sunlight exposure. For non-melanoma skin cancer there is substantial evidence that chronic exposure to the ultraviolet B radiation (UVB) (280-320 nm) portion of the sunlight spectrum is responsible. Experimentally, UVB is mutagenic and chronic UVB exposure can cause non-melanoma skin cancer in laboratory animals. Non-melanoma tumors in animals and in humans show characteristic UVB signature lesions in the tumor suppressor p53 and/or in the patched (PTCH) gene. An action spectrum or wavelength dependence for squamous cell carcinoma in the mouse shows a major peak of efficacy in the UVB. For malignant melanoma, however, the situation is unclear and the critical direct target(s) of sunlight in initiating melanoma and even the wavelengths responsible are as yet unidentified. This lack of information is in major part a result of a paucity of animal models for melanoma which recapitulate the role of sunlight in initiating this disease. The epidemiology of melanoma differs significantly from non-melanoma skin cancer. Intense sporadic sunlight exposure in childhood, probably exacerbated by additional adult exposure, is associated with elevated melanoma risk. Melanoma is also a disease of gene-environment interactions with underlying genetic factors playing a significant role. These major differences indicate that extrapolation from information for non-melanoma skin cancer to melanoma is unlikely to be useful. We summarize in this review the experimental information available on the role of UV radiation in melanoma and give an overview of animal melanoma models. A new model derived by neonatal UV irradiation of hepatocyte growth factor/scatter factor (HGF/SF) transgenic mice is described which recapitulates the etiology, the histopathology and molecular pathogenesis of human disease. It is anticipated that the HGF/SF transgenic model will provide a means to access the mechanism(s) by which sunlight initiates this lethal disease and provide an appropriate vehicle for derivation of appropriate therapeutic and preventive strategies.

Animals↗
PubMed2000

Insights from mouse models into the molecular basis of neurodegeneration.

Thanks largely to cloning the genes for several neurodegenerative diseases over the past decade and the existence of mouse mutants, the molecular basis of neurodegeneration is finally beginning to yield some of its secrets. We discuss what has been learned about the pathogenesis of "triplet repeat" diseases through mouse models for spinocerebellar ataxia types 1 and 3 and Huntington disease, including the roles of nuclear aggregates and protein cleavage. We also discuss the neurologic phenotypes that arise from mutations in neurotransmitter receptors (lurcher mice) and ion channels (weaver, leaner, and tottering mice), drawing parallels between ischemic cell death and the neurodegeneration that occurs in the lurcher mouse. Finally, we discuss common mechanisms of cell death and lessons learned from these mouse models that might have broader relevance to other neurologic disorders.

Animals↗
PubMed2002

Eotaxin protein levels and airway pathology in a mouse model for allergic asthma.

Eotaxin is a chemokine implicated in eosinophil trafficking and may be involved in the development of airway hyperresponsiveness. The role of eotaxin in a mouse model for allergic asthma was investigated. Challenging ovalbumin-sensitised mice with ovalbumin aerosol leads to airway hyperresponsiveness and airway eosinophilia 24 h after the last challenge. Furthermore, eotaxin concentrations were markedly increased in lungs and broncho-alveolar lavage fluid of ovalbumin-challenged mice compared to vehicle treated mice. This could mean that eotaxin is implicated in the pathology of this model. To further investigate the role of eotaxin in this murine model for allergic asthma, the ovalbumin response was modulated by either treatment with eotaxin antibodies or additional eotaxin, to suppress or promote the development of airway hyperresponsiveness and inflammation. Administration of eotaxin antibodies or an additional intravenous eotaxin injection did not alter the development of ovalbumin-induced airway hyperresponsiveness and eosinophilia. In conclusion, eotaxin concentrations were increased in a murine model for allergic airway inflammation. However, anti-eotaxin antibodies or additive intravenous murine eotaxin did not influence airway inflammation and hyperresponsiveness in this mouse model for allergic asthma.

Allergens↗
PubMed1999

Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model.

OBJECTIVE: To investigate the effects of retrovirus-based gene delivery of inhibitory cytokines and cytokine inhibitors into human synovial fibroblasts in the SCID mouse model of rheumatoid arthritis (RA). METHODS: The MFG vector was used for gene delivery of tumor necrosis factor alpha receptor (TNFalphaR) p55, viral interleukin-10 (IL-10), and murine IL-10 into RA synovial fibroblasts. The effect on invasion of these cells into human articular cartilage and on perichondrocytic cartilage degradation was examined after 60 days of coimplantation into the SCID mouse. RESULTS: TNFalphaR p55 gene transfer showed only a limited effect on inhibition of RA synovial fibroblast invasiveness and cartilage degradation. In contrast, invasion of the RA synovial fibroblasts into the coimplanted cartilage was strongly inhibited by both viral and murine IL-10. Perichondrocytic cartilage degradation was not affected by either form of IL-10. CONCLUSION: The data show that cytokines can be successfully inserted into the genome of human RA synovial fibroblasts using a retroviral vector delivery system, and that the SCID mouse model of human RA is a valuable tool for examining the effects of gene transfer. In addition, inhibition of more than one cytokine pathway may be required to inhibit both synovial- and chondrocyte-mediated cartilage destruction in RA.

Animals↗
PubMed1997

A mouse model of embolic focal cerebral ischemia.

We developed a mouse model of embolic focal cerebral ischemia, in which a fibrin-rich clot was placed at the origin of the middle cerebral artery (MCA) in C57BL/6J mice (n = 31) and B6C3 mice (n = 10). An additional three non-embolized C57BL/6J mice were used as a control. Embolus induction, cerebral vascular perfusion deficit, and consequent ischemic cell damage were confirmed by histopathology, immunohistochemistry, laser confocal microscopy, and regional cerebral blood flow (rCBF) measurements. Reduction in rCBF and cerebral infarct were not detected in the control animals. An embolus was found in all C57BL/6J and B6C3 mice at 24 hours after injection of a clot. Regional CBF in the ipsilateral parietal cortex decreased to 23% (P < 0.05) and 17% (P < 0.05) of preembolization levels immediately and persisted for at least 1 hour in C57BL/6J mice (n = 6) and in B6C3 mice (n = 3), respectively. A significant decrease of rCBF was accompanied by a corresponding reduction of plasma perfusion in the ipsilateral MCA territory. Neurons exhibited marked reduction in microtubule-associated protein-2 immunostaining coincident with the area of perfusion deficit. The percent infarct volume was 30.3% +/- 13.4% for C57BL/6J mice (n = 17), and 38.3% +/- 15.3% for B6C3 mice (n = 7) at 24 hours after embolization. This model of embolic ischemia is relevant to thromboembolic stroke in humans and may be useful to investigate embolic cerebral ischemia in the genetically altered mouse and for evaluation of antiembolic therapies.

Animals↗
PubMed2000

Up-regulation of cartilage oligomeric matrix protein at the onset of articular cartilage degeneration in a transgenic mouse model of osteoarthritis.

OBJECTIVE: To investigate the suitability of cartilage oligomeric matrix protein (COMP) as a marker for articular cartilage degeneration in a transgenic mouse model of osteoarthritis (OA). METHODS: Northern blot analysis of total RNA extracted from the knee joints of transgenic Del1 mice, which harbor a short deletion in a type II collagen transgene, and of their nontransgenic littermates was used to monitor changes in COMP messenger RNA (mRNA) levels during cartilage degeneration. Immunohistochemistry was used to determine the distribution of COMP in articular cartilage, and serum levels of COMP were measured by immunoassay. RESULTS: Transient up-regulation of COMP mRNA was seen in articular cartilage of transgenic Del1 mice at the onset of OA lesions at the age of 3 months. Compared with nontransgenic controls, COMP immunostaining of articular cartilage in 3-9-month-old transgenic mice was increased, especially at the border of uncalcified and calcified cartilage. There was also a change from predominantly interterritorial to pericellular/territorial deposition of COMP. This difference persisted until the age of 15 months, when the nontransgenic controls also demonstrated articular cartilage degeneration and increased COMP immunostaining. Increased serum levels of COMP were seen in Del1 mice at the age of 4 months, correlating temporally with the onset of cartilage degeneration. CONCLUSION: These findings suggest that upregulation of COMP mRNA and redistribution of the protein are characteristic of the early stages of articular cartilage degeneration in the transgenic mouse model in which OA results from a dominant-negative mutation in the type II collagen gene. The data provide additional support for the notion that COMP is a useful marker for altered cartilage metabolism in developing OA.

Animals↗
PubMed1987

Transgenic mouse model: a new approach for the investigation of endocrine pancreatic B-cell growth.

The transformation and adaptation of pancreatic insulin-producing (B) cells has been studied in a transgenic mouse model using a panel of antisera recognising peptides and general neuroendocrine markers at both light and electron microscopical levels. Stages of tumour genesis in the transgenic mouse model from hyperplasia to neoplasia, have been compared with human B-cell tumours. A normal complement of peptide containing cells was seen in the transgenic mouse pancreas, but cells containing pro-insulin-derived peptides became more numerous as hyperplasia commenced. The transgenic mouse tumours were composed of B cells, although 30-35% of the tumours were also found to contain PP cells--a finding which is directly comparable with that in human insulin-producing tumours. NSE, 7B2 and chromogranin immunoreactivities were found in most cells from all the tumours examined. Antisera to PGP 9.5, a novel marker for elements of the neuroendocrine system, were found to stain hyperplastic and neoplastic B-cells intensely. In contrast, normal mouse B-cells did not show PGP 9.5 immunoreactivity thus it appears that PGP 9.5 is differentially expressed in transformed and/or growing mouse B-cells and hence may be used as an indicator in studies of early tumour growth.

Adenoma, Islet Cell↗
PubMed2003

Establishment of a nude mouse model of hepatic metastasis for evaluation of targeted retroviral gene delivery.

BACKGROUND AND OBJECTIVES: The goal of this study was to establish a reproducible nude mouse model of liver metastasis and investigate the potential of deploying targeted injectable retroviral vectors for metastatic gastrointestinal cancer. METHODS: Human cancer cells were injected into the portal vein via an indwelling catheter. The animals were sacrificed at specified time intervals, and the number of tumor nodules was counted in histologic sections of harvested livers. A group of animals received either an extracellular matrix-targeted or a nontargeted retroviral vector bearing a beta-galactosidase gene by portal vein infusion. RESULTS: The number of tumor nodules increased progressively over time at </=50 days post-infusion (r = 0.81; P < 0.0001). Transduction of tumor nodules was observed in the animals that received a matrix-targeted, but not a nontargeted, vector. CONCLUSIONS: We have established a reproducible nude mouse model of liver metastasis, and demonstrated the feasibility of gene delivery to metastatic tumor nodules in vivo by portal vein infusions of a matrix-targeted retroviral vector.

Animals↗
PubMed1993

Delayed-type hypersensitivity response to the human papillomavirus type 16 E7 protein in a mouse model.

To study the immune response to human papillomavirus type 16, a mouse model was developed using a mouse keratinocyte cell line expressing the E7 protein. This line was grafted onto syngeneic mice to form a differentiated epithelium, thus closely mimicking the natural infection. A delayed-type hypersensitivity response could be demonstrated after intradermal challenge with a vaccinia virus recombinant expressing the E7 protein. This response appeared to be specific for the E7 polypeptide and was mediated by CD4+ cells.

Animals↗
PubMed2003

Amyloid-beta immunization in Alzheimer's disease transgenic mouse models and wildtype mice.

Alzheimer's disease is the most prevalent form of dementia worldwide. Therapies are desperately needed to prevent and cure the disease. Mouse models of amyloid-beta deposition [APP and PSAPP transgenic (tg) mice] have been useful in determining the role of amyloid-beta (A beta) in both the pathogenesis and cognitive changes in AD. In addition, they have allowed scientists to investigate potential AD therapies in living animals. Active and passive A beta immunizations have been employed successfully in APP and PSAPP tg mice to lower cerebral A beta levels and improve cognition. Optimization of immunization protocols and characterization of immune responses in wildtype mice have been reported. Based on the promising results of A beta immunization studies in mice, a clinical trial was initiated for A beta vaccination in humans with AD. Although no adverse effects were reported in the Phase I safety trials, about 5% of AD patients in the phase II clinical trial developed meningoencephalitis, ending the trial prematurely in March 2002. Studies in AD mouse models and wildtype mice may help elucidate the mechanism for these unwanted side effects and will be useful for testing newer, safer vaccines for future use in human clinical trials.

Alzheimer Disease↗
PubMed2000

Cerebral protein synthesis in a genetic mouse model of phenylketonuria.

Local rates of cerebral protein synthesis (lCPS(leu)) were measured with the quantitative autoradiographic [1-(14)C]leucine method in a genetic mouse model (Pah(enu2)) of phenylketonuria. As in the human disease, Pah(enu2) mice have a mutation in the gene for phenylalanine hydroxylase. We compared adult homozygous (HMZ) and heterozygous (HTZ) Pah(enu2) mice with the background strain (BTBR). Arterial plasma concentrations of phenylalanine (Phe) were elevated in both HMZ and HTZ mutants by 21 times and 38%, respectively. In the total acid-soluble pool in brain concentrations of Phe were higher and other neutral amino acids lower in HMZ mice compared with either HTZ or BTBR mice indicating a partial saturation of the l-amino acid carrier at the blood brain barrier by the elevated plasma Phe concentrations. In a series of steady-state experiments, the contribution of leucine from the arterial plasma to the tRNA-bound pool in brain was found to be statistically significantly reduced in HMZ mice compared with the other groups, indicating that a greater fraction of leucine in the precursor pool for protein synthesis is derived from protein degradation. We found reductions in lCPS(leu) of about 20% throughout the brain in the HMZ mice compared with the other two groups, but no reductions in brain concentrations of tRNA-bound neutral amino acids. Our results in the mouse model suggest that in untreated phenylketonuria in adults, the partial saturation of the l-amino acid transporter at the blood-brain barrier may not underlie a reduction in cerebral protein synthesis.

Animals↗
PubMed1994

Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjögren's syndrome.

PURPOSE: Previous research has demonstrated that testosterone therapy causes a profound suppression of autoimmune disease in lacrimal glands of female mouse models of Sjögren's syndrome. The aim of the present study was to determine whether other anabolic androgens, nonandrogenic steroids, or immunosuppressive agents might duplicate this hormonal effect. For comparative purposes, we also evaluated the influence of these various pharmacologic compounds on the tear volume, the magnitude of lymphocyte infiltration in the submandibular gland, and the extent of mucosal and peripheral lymphadenopathy. METHODS: Female MRL/MpJ-lpr/lpr mice were administered vehicle, steroids, or immunosuppressive compounds for 21 days after the onset of disease. Lacrimal glands and tears, as well as submandibular glands, spleens, and superior cervical and mesenteric lymph nodes were collected immediately before or after treatment and then processed for analysis. RESULTS: Our results showed that: (1) the immunosuppressive impact of testosterone on lymphocyte infiltration in lacrimal tissue was reproduced by the administration of 19-nortestosterone or cyclophosphamide, but not by therapy with 17 beta-estradiol, danazol, the experimental steroid Org 4094, cyclosporine A or dexamethasone; (2) treatment with testosterone, 19-nortestosterone, cyclophosphamide, or dexamethasone significantly reduced the extent of inflammation in salivary glands; (3) exposure to cyclophosphamide markedly diminished the size of lymphatic and splenic tissues, whereas glucocorticoid treatment only decreased the weight of superior cervical lymph nodes; and (4) administration of 17 beta-estradiol, Org 4094, or dexamethasone led to a significant decrease in tear volume. CONCLUSIONS: Overall, these results demonstrate that androgen or cyclophosphamide therapy may successfully ameliorate autoimmune expression in lacrimal and salivary glands of a female mouse model of Sjögren's syndrome.

Animals↗
PubMed1994

Age, environment, and lymphocyte immunization influence the spontaneous resorption rate in the CBA/J x DBA/2J mouse model.

PROBLEM: This study was designed to examine the influence of age, environment, and lymphocyte immunotherapy on fetal resorption rates in the CBA/J x DBA/2J mouse model. METHODS: After weaning, CBA/J female mice were randomly allocated to two different environments: room A was a conventional housing facility, and room B was a specific pathogen-free room. They were further divided into two groups in each room according to age (> three months and < or = three months), and mated with CBA/J, DBA/2J, or BALB/c males. The fetal resorption rates were observed. The immunization study was conducted using CBA/J females greater than three months old in room B. Preimmunization with various preparations and dosages of lymphocytes was performed 1 wk before mating with DBA/2J males, and fetal resorption rates were measured to investigate the effect of immunotherapy. RESULTS: In room A, the fetal resorption rates (9.4 to 11.8%) were not significantly different among the various mating combinations using CBA/J females greater or less than three months of age. In room B, CBA/J females older than three months and mated with DBA/2J males had a higher rate of fetal resorption than those younger than three months (28.9 versus 14.2%) and had higher rate of fetal resorption than those housed and mated in room A (28.9 versus 10.9%). This fetal resorption rate was also higher than those seen with other mating combinations. Preimmunization with male BALB/c splenic lymphocytes (optimal dose 1 x 10(7) cells) was effective in decreasing fetal resorption rate (7.9%), whereas administration of normal saline, or immunization with male CBA/J or DBA/2J lymphocytes was not (20.7 to 27.0%). CONCLUSION: Age and environment influence the spontaneous resorption rate in the CBA/J x DBA/2J mouse model. The high fetal resorption rate of older CBA/J females mated with DBA/2J males in a pathogen-free environment can be reduced by immunization with BALB/c splenic lymphocytes. These results suggested that a variety of mechanisms might initiate early pregnancy failure and that immunological modulation during implantation might be a nonspecific factor.

Abortion, Spontaneous↗
PubMed1986

Effect of thyroid hormone and sex status on epidermal growth factor concentrations in the submandibular gland of a congenitally hypothyroid mouse model.

Studies were performed to explore the role of thyroid hormone and sex status on epidermal growth factor concentrations in the submandibular gland of a congenitally hypothyroid mouse model designated hyt/hyt. The animals were studied at 20, 30 and 40 days of postnatal age. The euthyroid animals were homozygous or heterozygous for the hypothyroid gene. The homozygous euthyroid animals displayed a pattern of submandibular gland epidermal growth factor concentrations similar to those previously described in other mouse species and showed the expected sex differences. The hypothyroid animals had measurable but very low submandibular gland epidermal growth factor concentrations without sexual dimorphism. Serum thyroxine concentrations in the heterozygotes were comparable to those in the homozygous euthyroid animals, yet the animals had a delayed increase in epidermal growth factor concentrations combined with a later expression of female-male differences. The timing of the sex differences in submandibular gland epidermal growth factor concentrations followed a pattern similar to that seen for the timing of the first litter in these three genetically distinct groups. This infers the timing of the onset of puberty and suggests a role of androgens in the changes seen in epidermal growth factor concentrations. We conclude that thyroid hormone and sex status in this mouse model influence the pattern and concentrations of submandibular gland epidermal growth factor concentrations.

Animals↗
PubMed1997

Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma.

In patients with asthma, elevations of IgE correlate both with allergic inflammation of the airways and with bronchial hyperreactivity (BHR). Several investigations, using mouse models of this disease, have indicated a central role for IgE in the pathogenesis of the eosinophilic inflammation as well as in the obstructive airway physiology of BHR. Some diagnostic studies and therapeutic strategies for asthma are based on the putative role of IgE in asthma pathogenesis. Here, we use mice with a null mutation of the C epsilon locus to show that bronchial inflammation and BHR in response to allergen inhalation both can occur in the absence of IgE. We demonstrate that the eosinophilic bronchial inflammation elicited in an established mouse model of hypersensitivity to Aspergillus fumigatus (Af) is accompanied by the asthmatic physiology of BHR. Wild-type and IgE-deficient mice were sensitized intranasally with Af extract. Both groups of animals developed bronchoalveolar lavage eosinophilia and pulmonary parenchymal eosinophilia. This was accompanied by increased serum levels of total and Af-specific IgE in the wild-type animals only. This Af-sensitization protocol resulted in significant BHR in both wild-type mice and IgE-deficient mice. Interestingly, unsensitized IgE-deficient mice had increased bronchial responsiveness compared with unsensitized wild-type controls. We conclude that BHR and airways inflammation can be fully expressed via IgE-independent mechanisms. These may involve the activation of mast cells by factors other than IgE as well as a mucosal lymphocyte-mediated immune response to allergen.

Allergens↗
PubMed2001

Mouse models for multistep tumorigenesis.

The mouse is an ideal model system for studying the molecular mechanisms underlying the pathogenesis of human cancer. The generation of transgenic and gene-knockout mice has been instrumental in determining the role of major determinants in this process, such as oncogenes and tumor-suppressor genes. In the past few years, modeling cancer in the mouse has increased in its complexity, allowing in vivo dissection of the fundamental concepts underlying cooperative oncogenesis in various tumor types. In this review, we discuss how this transition has been facilitated, providing relevant examples. We also review how, in the post-genome era, novel methodologies will further accelerate the study of multi-step tumorigenesis in the mouse.

Animals↗
PubMed2000

Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis.

The neu (c-erbB-2, Her-2) protooncogene is amplified and overexpressed in 20-30% of human breast cancers. Although transgenic mouse models have illustrated the role of Neu in the induction of mammary tumors, Neu expression in these models is driven by a strong viral promoter of questionable relevance to the human disease. To ascertain whether expression of activated Neu under the control of the endogenous promoter in the mammary gland could induce mammary tumors we have generated mice that conditionally express activated Neu under the transcriptional control of the intact endogenous Neu promoter. Expression of oncogenic neu in the mammary gland resulted in accelerated lobulo-alveolar development and formation of focal mammary tumors after a long latency period. However, expression of activated Neu under the normal transcriptional control of the endogenous promoter was not sufficient for the initiation of mammary carcinogenesis. Strikingly, all mammary tumors bear amplified copies (2-22 copies) of the activated neu allele relative to the wild-type allele and express highly elevated levels of neu transcript and protein. Thus, like human erbB-2-positive breast tumors, mammary tumorigenesis in this mouse model requires the amplification and commensurate elevated expression of the neu gene.

Animals↗