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PubMed1987

Campylobacter diarrhea in an adult mouse model.

An adult mouse (18-20 g) model was developed for studying the pathogenesis of Campylobacter isolates. Iron-loaded BALB/c mice given 10(8)-10(9) Campylobacter colony forming units by intraperitoneal injection developed a severe mucoid diarrhea within 4 h. Severe diarrhea, consisting of unformed stools containing blood, mucus, and fecal leukocytes, persisted for 24 h. Diarrheal symptoms in surviving mice resolved gradually; no diarrhea was observed 5 days after inoculation. Mice not pretreated with iron developed no diarrheal symptoms, and no severe diarrhea was produced in mice inoculated orally. A transient (less than 24 h) bacteremia occurred in mice inoculated either orally or intraperitoneally. Liver, spleen, and kidney were positive for Campylobacter for 48 h; intestinal contents were positive for 5-7 days. Mice given greater than or equal to 10(10) colony forming units showed symptoms of endotoxemia (ruffled fur, inactivity, shaking, tearing, and hypothermia) and died without diarrheal symptoms. Mice given nonpathogenic Escherichia coli strain HB101, heat-killed C. jejuni cells (greater than 10(10)), C. jejuni lipopolysaccharide extract, or purified lipopolysaccharide from either Vibrio cholerae 569B or Salmonella typhimurium showed no diarrheal symptoms.

Animals↗
PubMed1993

Detection of chemical mutagens using Muta Mouse: a transgenic mouse model.

A transgenic mouse strain with a high copy number of rescuable lacZ sequences was evaluated for its effectiveness in detecting lacZ- mutations in selected tissues. Procarbazine, cyclophosphamide, ethylnitrosourea, 7,12-dimethylbenz[a]anthracene (DMBA), acrylamide and chlorambucil were tested following either single or repeated dosing regimens. Bone marrow, liver, skin and testis tissues were selected to assess as target sites for mutation. Bone marrow, liver and testis tissues were examined for mutation following exposures to ethylnitrosourea and chlorambucil. Increased mutant frequencies were found for both chemicals in all three tissues. Bone marrow tissue was examined for mutation following procarbazine, cyclophosphamide and acrylamide exposures, and skin was examined for mutation following dermal application of DMBA. Mutation induction was observed in all cases. The results obtained from this investigation demonstrate the applicability of this transgenic mouse as an effective model to detect and analyze gene mutation in selected organs including germinal tissues. Studies of organotrophic chemical mutagens and carcinogens are possible with this model as are studies of the susceptibility of germinal tissues to mutagen exposures.

Animals↗
PubMed2006

Behavioral phenotyping of mouse models of neurodevelopmental disorders: relevant social behavior patterns across the life span.

Social responses are a key element for behavioral phenotyping of mouse models of neurodevelopmental disorders associated with social deficits. Here we describe selected behavioral responses that can be measured in developing and adult mice, with special emphasis on ultrasonic vocalizations, a behavioral response not yet systematically characterized in most of the genetic mouse models of social abnormalities. A recently developed task to measure social approach relevant to the first core symptom of autism is highlighted. We also focus on those developmental factors, including litter size, litter composition, and early social milieu, that are often underestimated when measuring adult social behavior in mouse models of neurodevelopmental disorders. We present a summary of available data concerning social behavioral responses in mice with targeted gene mutations. We conclude by suggesting that assessment of early behavioral traits, and corresponding relationships with adult behavioral profiles, could be a useful strategy to investigate mouse models of neurodevelopmental disorders associated with social deficits.

Animal Communication↗
PubMed2006

Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of beta-amyloid (Abeta)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Abeta42/Abeta40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until approximately 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.

Aging↗
PubMed2006

Genetically modified mouse models in studies of luteinising hormone action.

Numerous genetically modified mouse models have recently been developed for the study of the pituitary-gonadal interactions. They include spontaneous or engineered knockouts (KO) of the gonadotrophin-releasing hormone (GnRH) and its receptor, the gonadotrophin common-alpha(Calpha), luteinising hormone (LH) beta and follicle-stimulating hormone (FSH) beta subunits, and the two gonadotrophin receptors (R), LHR and FSHR. In addition, there are also transgenic (TG) mice overexpressing gonadotrophin subunits and producing supraphysiological levels of these hormones. These models have offered relevant phenocopies for similar mutations in humans and to a great extent expanded our knowledge on normal and pathological functions of the hypothalamic-pituitary-gonadal (HPG) axis. The purpose of this article is to review some of our recent findings on two such mouse models, the LHR KO mouse (LuRKO), and the hCG overexpressing TG mouse (hCG+).

Animals↗
PubMed2003

Mouse models of human cancer web-based resources.

The Mouse Models of Human Cancers Consortium (MMHCC) is a collaborative program designed to derive and characterize mouse models of human malignancies. To enhance information and resource exchange among the MMHCC investigators and other cancer research scientists, the NCI Center for Bioinformatics (NCICB, http://ncicb.nci.nih.gov/) has developed web-based resources that are freely available to the cancer research community. These resources include a website (http://emice.nci.nih.gov) and databases for cancer models (http://cancermodels.nci.nih.gov) and cancer images (http://cancerimages.nci.nih.gov).

Animals↗
PubMed2002

Mouse models for human deafness: current tools for new fashions.

Mouse models are one of the major tools used for discovery and characterization of genes for non-syndromic deafness in humans. The similarities between the mouse and human genomes, and between the physiology and morphology of their auditory systems, are striking. This article describes the latest mouse models, including spontaneous, 'knockout' and ENU (N-ethyl-N-nitrosourea)-induced mutants, and the recent discovery of modifier genes that are involved in mouse deafness; this discovery is leading the search for genetic modifiers for human disorders.

Animals↗
PubMed2001

Understanding the pathogenesis of allergic asthma using mouse models.

OBJECTIVE: This paper reviews the current views of the pathogenesis of airway eosinophilic inflammation and airway hyperresponsiveness (AHR) in allergic asthma based on mouse models of the disease. The reader will also encounter new treatment strategies that have arisen as this knowledge is applied in practice. DATA SOURCES: MEDLINE searches were conducted with key words asthma, mouse model, and murine. Additional articles were identified from references in articles and book chapters. STUDY SELECTION: Original research papers and review articles from peer-reviewed journals were chosen. RESULTS: Although the mouse model does not replicate human asthma exactly, the lessons learned about the pathogenesis of allergic airway inflammation and AHR are generally applicable in humans. Type 2 T helper lymphocytes (Th2) orchestrate the inflammation and are crucial for the development of AHR. Cells and molecules involved in T cell activation (dendritic cells, T cell receptor, major histocompatibility complex molecule, and costimulatory molecules) are also vital. Besides these, no other cell or molecule could be shown to be indispensable for the establishment of the model under all experimental conditions. There are at least three pathways that lead to AHR. One is dependent on immunoglobulin E and mast cells, one on eosinophils and interleukin-5 (IL-5), and one on IL-13. Eosinophils are probably the most important effector cells of AHR. Radical methods to treat asthma have been tested in the animal model, including modifying the polarity of lymphocyte response and antagonizing IL-5. CONCLUSIONS: AHR, the hallmark of asthma, is attributable to airway inflammation ultimately mediated by helper T cells via three pathways, at least. The mouse model is also a valuable testing ground for new therapies of asthma.

Animals↗
PubMed2003

Lung proteome alterations in a mouse model for nonallergic asthma.

A mouse model for nonatopic asthma was employed to study the alterations of the lung proteome to gain insight into the underlying molecular mechanisms of disease pathophysiology post-challenge. Lung samples from asthmatic and control mice were used to generate 24 high quality two-dimensional electrophoresis gels wherein 2115 proteins were examined for disease relevance. In total, 23 proteins were significantly up- or down-regulated following hapten-challenge of dinitro-fluorobenzene-hypersensitive mice. Twenty proteins were identified by mass spectrometry, of which 18 could be linked to asthma related symptoms, such as stress and inflammation, lung detoxification, plasma exudation and/or tissue remodeling. As such, proteomics was clearly vindicated as a means of studying this complex disease phenomenon. The proteins found in this study may not necessarily play a role in the immunological mechanisms and/or pathophysiology of asthma development. However, they may prove useful as surrogate biomarkers for quantitatively monitoring disease state progression or response to therapy. The mathematics of achieving statistical confidence from low numbers of gel replicates containing large numbers of independent variables stress the need for high numbers of replicates to better sample the population of proteins revealed by two-dimensional gel electrophoresis.

Actins↗
PubMed1993

Evaluation of vaccines and of antigen therapy in a mouse model for Brucella ovis.

A mouse model was developed to study Brucella ovis infection. The evolution of the number of B. ovis per spleen of mice inoculated intravenously, intraperitoneally or subcutaneously was found to be independent of the sex of the mice. The number of B. ovis increased in the spleen when increasing the challenge dose up to 1.7 x 10(7). At higher doses of challenge, the response remained constant. In this model it was observed that the inoculation of Brucella melitensis Rev 1 vaccine or subcellular B. ovis hot saline antigens during both the acute and chronic phases did not modify the time course of B. ovis infection. Finally, the model was found suitable to determine the efficacy of anti-B. ovis vaccines. B. melitensis Rev 1 (2.2 x 10(5) c.f.u.) and B. suis strain 2 (1.2 x 10(7) c.f.u.) live vaccines but not the inactivated B. melitensis H38 vaccine conferred protection against B. ovis.

Animals↗
PubMed2006

Vascular endothelial growth factor and matrix metalloproteinase-2 expedite formation of endometriosis in the early stage ICR mouse model.

OBJECTIVE: To establish a mouse model for endometriosis and to evaluate roles of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) in the formation of disease. DESIGN: Experimental laboratory study. SETTING: A women's hospital in China. PATIENT(S) AND ANIMAL(S): Ten women with endometriosis and 10 control women, as well as ICR mice. INTERVENTION(S): Endometrial fragments were transplanted in the peritoneal cavities of mice at minilaparotomy. Transplants were observed and then removed for the assessment of morphology and immunohistochemical staining of VEGF and MMP-2. MAIN OUTCOME MEASURE(S): Observation of transplants, expression of VEGF and MMP-2. RESULT(S): On days 1 and 2, glandular and stromal cells were viable at the margins of transplants. On day 3, the transplants were surrounded by mesothelial cells, and the endometrial glands and stromal cells were clearly viable at the interface. The scores of VEGF and MMP-2 of viable glandular cells of transplants were increased compared with the ones before transplantation. The scores of VEGF and MMP-2 of transplants from women with endometriosis were higher than those of control women. CONCLUSION(S): Endometrial transplants from the patients with endometriosis express more VEGF and MMP-2 than endometrium in control women, suggesting that VEGF and MMP-2 may expedite the formation of endometriosis in its early stage.

Animals↗
PubMed2004

In vivo positron-emission tomography imaging of progression and transformation in a mouse model of mammary neoplasia.

Imaging mouse models of human cancer promises more effective analysis of tumor progression and reduction of the number of animals needed for statistical power in preclinical therapeutic intervention trials. This study utilizes positron emission tomography imaging of 2-[18F]-fluoro-deoxy-D-glucose to monitor longitudinal development of mammary intraepithelial neoplasia outgrowths in immunocompetent FVB/NJ mice. The mammary intraepithelial neoplasia outgrowth tissues mimic the progression of breast cancer from premalignant ductal carcinoma in situ to invasive carcinoma. Progression of disease is clearly evident in the positron emission tomography images, and tracer uptake correlates with histological evaluation. Furthermore, quantitative markers of disease extracted from the images can be used to track proliferation and progression in vivo over multiple time points.

Animals↗
PubMed2006

RNAIII-inhibiting peptide in combination with the cathelicidin BMAP-28 reduces lethality in mouse models of staphylococcal sepsis.

A mouse model of staphylococcal sepsis was used to evaluate the efficacy of RNAIII-inhibiting peptide (RIP) combined with the cathelicidin BMAP-28. Preliminary in vitro studies showed that both peptides, alone or combined, were able to inhibit the lipoteichoic acid-induced production of tumor necrosis factor alpha and nitric oxide by RAW 264.7 cells. For in vivo experiments, the main outcome measures were lethality, quantitative blood cultures, and detection of tumor necrosis factor alpha and interleukin 6 plasma levels. BALB/c mice were injected i.v. with 2.0 x 10(6) colony-forming units of live Staphylococcus aureus ATCC 25923 or with 5.0 x 10(8) heat-killed cells of the same strain. All animals were randomized to receive i.v. isotonic sodium chloride solution, 10-mg/kg RIP, alone or in combination with 2-mg/kg BMAP-28, 7-mg/kg imipenem, or 7-mg/kg vancomycin, immediately and at 6 hours after bacterial challenge. In in vivo experiments performed with live bacteria, all compounds reduced lethality rates and bacteremia when compared with controls. In general, combined-treated groups had significantly lower bacteremia when compared with single-treated groups. Lowest lethality rates and bacteremia were obtained when RIP was administered in combination with BMAP-28 or vancomycin. In the experiments performed using heat-killed organisms, only BMAP-28 demonstrated significant efficacy on lethality rates and cytokines plasma levels when compared with controls. RIP combined with BMAP-28 exhibited the highest efficacy on all main outcome measurements. These data were observed on both immediate and delayed treatments. These results highlight the capacity of RIP and BMAP-28 to reduce the septic effects of bacterial cell components and exotoxins, and suggest their potential use in the treatment of severe staphylococcus-associated sepsis.

Animals↗
PubMed2003

Gene therapy for human immunodeficiency virus infection in the humanized SCID mouse model.

BACKGROUND: The humanized SCID mouse model is an attractive tool for testing gene therapy to combat human immunodeficiency virus infection in vivo. OBJECTIVES: To devise a more specific gene therapy directed against HIV, replacing the formerly used interferon with either soluble CD4 molecule immunoadhesin (sCD4-IgG) and/or anti-gp41 monoclonal antibody (2F5), or HIV-negative transdominants genes (Tat, Rev). METHODS: Human monocytoid cell line (U937) was transfected with IFN alpha, beta or gamma genes. 3T3 murine fibroblastic cell line was transfected with sCD4-IgG or 2F5, or both genes, and a human T4 cell line (CEM) was grafted to SCID mice. Negative transdominant genes (Tat, Rev or both) were also transduced in CEM T cell line. Animals were then challenged with HIV-1, Viral load was followed. RESULTS: IFN alpha or beta were potent anti-HIV, reducing viral load in vivo and inhibiting reverse transcriptase activity in human-removed cells from animals. sCD4-IgG immunoadhesin and gp41 monoclonal antibody resulted in a dramatic reduction of HIV-1 cellular and plasmatic viral load in humanized SCID mice. The simultaneous introduction of negative Tat and Rev genes resulted in a synergistic inhibition of HIV-1 replication in vivo. CONCLUSIONS: Despite the marked reduction of HIV-1 propagation by IFN genes or by negative Tat and Rev transdominants, the gene therapy using soluble CD4 immunoadhesin or anti-gp41 was a more efficient preventive treatment against HIV infection.

Animals↗
PubMed1993

Poliovirus attenuation and pathogenesis in a transgenic mouse model for poliomyelitis.

A transgenic mouse model for poliomyelitis has been used to study aspects of poliovirus attenuation and pathogenesis. Transgenic mice expressing the cell receptor for poliovirus (TgPVR mice) develop poliomyelitis after inoculation with poliovirus by a variety of routes. TgPVR mice have been used to identify genomic sequences responsible for the attenuation phenotype of the P1/Sabin and P2/Sabin vaccine strains. Primary cell cultures derived from TgPVR mice differentiate between neurovirulent and attenuated virus strains, indicating that it may be possible to use these cultures to determine the functional basis of attenuation. Studies in TgPVR mice indicate that poliovirus tropism is not controlled solely by expression of PVR, and that poliovirus spreads from muscle to the central nervous system by neural pathways.

Animals↗
PubMed2004

Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee.

The Pathological Classification of Prostate Lesions in Genetically Engineered Mice (GEM) is the result of a directive from the National Cancer Institute Mouse Models of Human Cancer Consortium Prostate Steering Committee to provide a hierarchical taxonomy of disorders of the mouse prostate to facilitate classification of existing and newly created mouse models and the translation to human prostate pathology. The proposed Bar Harbor Classification system is the culmination of three meetings and workshops attended by various members of the Prostate Pathology Committee of the Mouse Models of Human Cancer Consortium. A 2-day Pathology Workshop was held at The Jackson Laboratory in Bar Harbor, Maine, in October 2001, in which study sets of 93 slides from 22 GEM models were provided to individual panel members. The comparison of mouse and human prostate anatomy and disease demonstrates significant differences and considerable similarities that bear on the interpretation of the origin and natural history of their diseases. The recommended classification of mouse prostate pathology is hierarchical, and includes developmental, inflammatory, benign proliferative, and neoplastic disorders. Among the neoplastic disorders, preinvasive, microinvasive, and poorly differentiated neoplasms received the most attention. Specific criteria were recommended and will be discussed. Transitions between neoplastic states were of particular concern. Preinvasive neoplasias of the mouse prostate were recognized as focal, atypical, and progressive lesions. These lesions were designated as mouse prostatic intraepithelial neoplasia (mPIN). Some atypical lesions were identified in mouse models without evidence of progression to malignancy. The panel recommended that mPIN lesions not be given histological grades, but that mPIN be further classified as to the absence or presence of documented associated progression to invasive carcinoma. Criteria for recognizing microinvasion, for classification of invasive gland-forming adenocarcinomas, and for characterizing poorly differentiated tumors, including neuroendocrine carcinomas, were developed and are discussed. The uniform application of defined terminology is essential for correlating results between different laboratories and models. It is recommended that investigators use the Bar Harbor Classification system when characterizing new GEM models or when conducting experimental interventions that may alter the phenotype or natural history of lesion progression in existing models.

Animals↗
PubMed1994

Comparison of corticosteroid- and L3T4+ antibody-immunosuppressed mouse models of Pneumocystis carinii pneumonia for evaluation of drugs and leukocytes.

An immunologically immunosuppressed mouse model of Pneumocystis carinii pneumonia using antibody developed by Dialynas et al. (Immunol. Rev. 74:29-55, 1983) directed to L3T4+ T cells (referred to as L3T4+ antibody) was compared with a corticosteroid-immunosuppressed mouse model. Corticosteroid- or L3T4+ antibody-immunosuppressed BALB/c mice transtracheally inoculated with P. carinii developed severe infections within 5 weeks after inoculation and responded to treatments with an echinocandin B analog, LY302146, or trimethoprim plus sulfamethoxazole so that they had decreased numbers of P. carinii cysts and trophozoites. LY302146 appeared to be more effective in L3T4+ antibody-immunosuppressed mice than in dexamethasone-immunosuppressed mice. Leukocyte populations in lungs of both mouse models during development of infection and during treatment were compared by using immune cell-specific staining. Lungs of L3T4+ antibody-immunosuppressed mice had many more cells detected with pan-B antibody and pan-T antibody than dexamethasone-immunosuppressed mice and the lungs of successfully treated mice had about the same numbers of macrophages as those of nonimmunosuppressed uninfected mice. The immunologically immunosuppressed model will allow study of cytokines and other immune modulators alone and in combination with drugs.

Animals↗
PubMed2005

A luciferase transgenic mouse model: visualization of prostate development and its androgen responsiveness in live animals.

Numerous mouse models of prostate carcinogenesis have been developed, but hitherto there has been no model in which the prostate gland could be imaged in live animals. The transgenic model generated here targeted mouse prostate gland using a firefly luciferase enzyme under the control of a small but highly active and specific supra prostate-specific antigen (sPSA) promoter. We evaluated postnatal prostate development, involution and androgen-induced restoration of prostate growth in adult transgenic mice using bioluminescence imaging. Results of our study showed that: (i) the prostate gland of male offspring did not yield a significant bioluminescence signal until after sexual maturity. Luciferase was detected in the luminal epithelial cells of the ventral and dorsolateral lobes of the prostate gland and caput epididymis, with little or no activity in 18 other organs evaluated. (ii) While a constant high level of bioluminescence was detected in the mouse prostate from 5 to 35 weeks of age, a slight drop in bioluminescence was detected at 36 to 54 weeks. (iii) Upon castration, the luciferase activity signal associated with mouse prostate detected by a cooled charge-coupled device camera was dramatically reduced. This signal could be rapidly restored to pre-castration levels after androgen administration. Androgen-induced luciferase activity subsided to nearly basal levels 5 days following the last injection. These data demonstrate that a bioluminescent mouse model with luciferase activity restricted to the prostate gland under the control of a (sPSA) promoter can be used on a real-time basis in live animals to investigate the development and responsiveness of the prostate gland to exogenously administered androgen. This model can be extended to detect the responsiveness of the prostate gland to therapy and used as a founder strain to visualize tumors in hosts with different genetic backgrounds.

Androgens↗