SEARCH · PubMed Health

Results for “Mouse Model”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources

PubMed2001

Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D.

Mouse chromosome 10 harbors several loci associated with hearing loss, including waltzer (v), modifier-of deaf waddler (mdfw) and Age-related hearing loss (Ahl). The human region that is orthologous to the mouse 'waltzer' region is located at 10q21-q22 and contains the human deafness loci DFNB12 and USH1D). Numerous mutations at the waltzer locus have been documented causing erratic circling and hearing loss. Here we report the identification of a new gene mutated in v. The 10.5-kb Cdh23 cDNA encodes a very large, single-pass transmembrane protein, that we have called otocadherin. It has an extracellular domain that contains 27 repeats; these show significant homology to the cadherin ectodomain. In v(6J), a GT transversion creates a premature stop codon. In v(Alb), a CT exchange generates an ectopic donor splice site, effecting deletion of 119 nucleotides of exonic sequence. In v(2J), a GA transition abolishes the donor splice site, leading to aberrant splice forms. All three alleles are predicted to cause loss of function. We demonstrate Cdh23 expression in the neurosensory epithelium and show that during early hair-cell differentiation, stereocilia organization is disrupted in v(2J) homozygotes. Our data indicate that otocadherin is a critical component of hair bundle formation. Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D.

Amino Acid Sequence↗

PubMed1980

A mouse model of Chlamydia trachomatis pneumonitis.

A mouse model for studying infections due to Chlamydia trachomatis is described. Pneumonitis was produced by intranasal inoculation of four trachoma and one lymphogranuloma venereum strains. The infection was confirmed by cell culture isolation of the organisms from the lung, detection of serum antibody and delayed hypersensitivity, and the observation of inclusions in the interstitial cells of the lung by light and electron microscopy. This study indicates that mice may serve as a useful nonprimate animal model for the study of the pathogenesis and immunology of C. trachomatis infection.

Animals↗

PubMed2004

The antimicrobial peptide BMAP-28 reduces lethality in mouse models of staphylococcal sepsis.

OBJECTIVE: A mouse model of staphylococcal sepsis was used to compare the efficacy of the bovine antimicrobial peptide BMAP-28, a compound of the cathelicidin family, with that of conventional antibiotics. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory in a university hospital. SUBJECTS: BALB/c male mice. INTERVENTIONS: BALB/c mice were injected intravenously 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 intravenously isotonic sodium chloride solution, 2 mg/kg BMAP-28, 7 mg/kg imipenem, 7 mg/kg vancomycin, 7 mg/kg clindamycin, and 7 mg/kg clarithromycin immediately and at 6 hrs after bacterial challenge. MEASUREMENTS AND MAIN RESULTS: Lethality, quantitative blood cultures, and detection of tumor necrosis factor-alpha and interleukin-6 plasma levels. In the experiments performed with live bacteria, all compounds reduced lethality rates and bacterial growth compared with controls. Imipenem and vancomycin exhibited the highest efficacy on these main outcome measures. In the experiments performed using heat-killed organisms, only BMAP-28 demonstrated significant efficacy on lethality rates, tumor necrosis factor-alpha, and interleukin-6 plasma levels compared with controls. CONCLUSION: These results highlight the capacity of BMAP-28 to reduce the effects of components of the bacterial cells and suggest that it may be beneficial in the treatment of severe staphylococcal infections in concert with other antimicrobial agents.

Analysis of Variance↗

PubMed1996

Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome.

A mouse model for the autosomal form of Alport syndrome was produced. These mice develop a progressive glomerulonephritis with microhematuria and proteinuria, consistent with the human disease. End-stage renal disease develops at approximately 14 weeks of age. TEM analysis of the glomerular basement membranes (GBM) during development of renal pathology revealed focal multilaminated thickening and thinning beginning in the external capillary loops at 4 weeks and spreading throughout the GBM by 8 weeks. By 14 weeks, half of the glomeruli were fibrotic with collapsed capillaries. Immunofluorescence analysis of the GBM showed the absence of type IV collagen alpha-3, alpha-4, and alpha-5 chains and a persistence of alpha-1 and alpha-2 chains (these chains normally localize to the mesangial matrix). Northern blot analysis using probes specific for the collagen chains illustrate the absence of COL4A3 in the knockout, whereas mRNAs for the remaining chains are unchanged. An accumulation of fibronectin, heparan sulfate proteoglycan, laminin-1, and entactin was observed in the GBM of the affected animals. The temporal and spatial pattern of accumulation was consistent with that for thickening of the GBM as observed by TEM. Thus, expression of these basement membrane-associated proteins may be involved in the progression of Alport renal disease pathogenesis. The levels of mRNAs encoding the basement membrane-associated proteins at 7 weeks were unchanged.

Animals↗

PubMed1999

Localization of the sites of conduction abnormalities in a mouse model of myotonic dystrophy.

INTRODUCTION: A mouse strain lacking functional myotonic dystrophy protein kinase (DMPK) has recently been developed. DMPK-/- mice exhibit muscular and conduction abnormalities consistent with the disease; however, the site of abnormal cardiac conduction is unknown. METHODS AND RESULTS: Nine homozygous DMPK-/- mice and seven age matched wild-type (WT) controls underwent in vivo electrophysiologic studies using an endocardial 2-French catheter. Baseline intervals as well as Wenckebach and 2:1 cycle lengths were measured to assess AV and ventriculoatrial (VA) conduction. Effective refractory periods (ERP) and functional refractory periods were determined during atrial and ventricular premature stimulation. His-bundle recordings were obtained on all the studied animals (16/16). DMPK-/- mice had significantly prolonged PR (48.1 +/- 5.5 vs 40.9 +/- 3.9 msec, P = 0.010) and AH (36.7 +/- 4.0 vs 31.6 +/- 4.8 msec, P = 0.037) intervals compared to WT controls. HV intervals were very significantly prolonged as well (14.7 +/- 2.0 vs 10.3 +/- 0.8 msec; P < 0.0001). Three of 9 DMPK-/- and 1 of 7 WT mice exhibited VA block. Atrial ERP was reached before AV node ERP in 2 (22%) of 9 of the knockout mice and 5 (71%) of 7 of the controls (P = 0.06). Only one mouse (DMPK-/-) exhibited infra-Hisian block on premature atrial stimulation. CONCLUSION: In this mouse model of myotonic dystrophy, AV conduction abnormalities were localized to the supra-Hisian and infra-Hisian conduction tissues, with a higher predilection to the latter, a finding similar to the human form of the disease.

Animals↗

PubMedDate not supplied

Imaging corneal pathology in a transgenic mouse model using nonlinear microscopy.

A transgenic mouse model with a Clim [co-factor of LIM (a combination of first letters of Lin-11 (C. elegans), ISL1 (rat), and Mec-3 (C. elegans) gene names) domain proteins] gene partially blocked in the epithelial compartment of its tissues is used to establish the sensitivity of intrinsic reflectance nonlinear optical microscopy (NLOM) to stromal and cellular perturbations in the cornea. Our results indicate dysplasia in the squamous epithelium, irregular collagen arrays in the stroma, and a compromised posterior endothelium in the corneas of these mice. As suggested by biochemical data, the collagen alterations are likely due to collagen III synthesis and deposition during healing and remodeling of transgenic mice corneal stromas. All of the topographic features seen in NLOM images of normal and aberrant corneas are confirmed by coregistration with histological sections. In this work, we also use ratiometric redox fluorometry based on two-photon excited cellular fluorescence from reduced nicotinamide adenine dinucleotide (NAD)(P)H and oxidized flavin adenine dinucleotide (FAD) to study mitochondrial energy metabolism. Employing this method, we detect higher metabolic activity in the endothelial layer of cornea compared to an epithelial layer located further away from the metabolites. The combination of two-photon excited fluorescence (TPF) with second harmonic generation (SHG) signals allows imaging to aid in understanding the relationship between alternation of specific genes and structural changes in cells and extracellular matrix.

Animals↗

PubMed1996

Development of a germfree mouse model of Vibrio cholerae infection.

A mouse model of Vibrio cholerae infection was successfully developed with germfree mice. Three- to four-week-old germfree mice were orally inoculated with strains of V. cholerae to be tested and then moved to normal housing after inoculation. Stool culture, measurement of serum vibriocidal antibody titers, and determination of immune responses to the cholera toxin B subunit demonstrated that germfree mice are readily colonized by V cholerae and develop systemic and mucosal immune responses to antigens expressed by these organisms. Immune responses to the B subunit of Shiga toxin 1, which was expressed from a V. cholerae vaccine vector, were less pronounced. This model should be valuable for studying immune responses to V. cholerae infection and immunization, including responses to heterologous antigens expressed by cholera vector strains.

Animals↗

PubMed2000

ANP in regulation of arterial pressure and fluid-electrolyte balance: lessons from genetic mouse models.

The recent development of genetic mouse models presenting life-long alterations in expression of the genes for atrial natriuretic peptide (ANP) or its receptors (NPR-A, NPR-C) has uncovered a physiological role of this hormone in chronic blood pressure homeostasis. Transgenic mice overexpressing a transthyretin-ANP fusion gene are hypotensive relative to the nontransgenic littermates, whereas mice harboring functional disruptions of the ANP or NPR-A genes are hypertensive compared with their respective wild-type counterparts. The chronic hypotensive action of ANP is determined by vasodilation of the resistance vasculature, which is probably mediated by attenuation of vascular sympathetic tone at one or several prejunctional sites. Under conditions of normal dietary salt consumption, the hypotensive action of ANP is dissociated from the natriuretic activity of the hormone. However, during elevated dietary salt intake, ANP-mediated antagonism of the renin-angiotensin system is essential for maintenance of blood pressure constancy, inasmuch as the ANP gene "knockout" mice (ANP -/-) develop a salt-sensitive component of hypertension in association with failure to adequately downregulate plasma renin activity. These findings imply that genetic deficiencies in ANP or natriuretic receptor activity may be underlying causative factors in the etiology of salt-sensitive variants of hypertensive disease and other sodium-retaining disorders, such as congestive heart failure and cirrhosis.

Animals↗

PubMed2004

A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer.

PURPOSE: A transgenic mouse model has revealed parameters of the angiogenic switch during multistep tumorigenesis of pancreatic islets, and demonstrated efficacy of antiangiogenic therapies. Pericytes have been revealed as functionally important for tumor neovasculature, using kinase inhibitors targeting their platelet-derived growth factor receptors (PDGFRs). Additionally, vascular endothelial growth factor receptor (VEGFR) inhibitors and metronomic chemotherapy show modest benefit against early- but not late-stage disease. MATERIALS AND METHODS: Seeking to improve efficacy against otherwise intractable end-stage pancreatic islet tumors, two receptor tyrosine kinase inhibitors, imatinib and SU11248, were used to disrupt PDGFR-mediated pericyte support of tumor endothelial cells in concert with maximum-tolerated dose (MTD) or metronomic chemotherapy and/or VEGFR inhibition. RESULTS: Imatinib, despite equivocal efficacy as monotherapy, reduced pericyte coverage of tumor vessels and enhanced efficacy in combination with metronomic chemotherapy or VEGFR inhibition. A regimen involving all three was even better. MTD using cyclophosphamide caused transitory regression, but then rapid regrowth, in contrast to metronomic cyclophosphamide plus imatinib, which produced stable disease. The MTD regimen elicited apoptosis of tumor cells but not endothelial cells, whereas the other regimens increased endothelial cell apoptosis concordant with efficacy. A "chemo-switch" protocol, involving sequential MTD and then metronomic chemotherapy, overlaid with multitargeted inhibition of PDGFR and VEGFR, gave complete responses and unprecedented survival advantage in this model. CONCLUSION: This study demonstrates a potentially tractable clinical strategy in a stringent preclinical model, wherein standard-of-care chemotherapy is followed by a novel maintenance regimen: PDFGR is targeted to disrupt pericyte support, while metronomic chemotherapy and/or VEGFR inhibitors target consequently sensitized endothelial cells, collectively destabilizing pre-existing tumor vasculature and inhibiting ongoing angiogenesis.

Adenoma, Islet Cell↗

PubMed1984

Activity of ceftizoxime and comparative compounds against Bacteroides fragilis in a mouse model of anaerobic infection.

A new mouse model of anaerobic infection with Bacteroides fragilis alone or in a mixed infection with Escherichia coli is described. It is established by implantation under the skin of a filter paper disk saturated with the appropriate bacterial suspension. The penetration of antibiotics into the implantation site can be detected by assaying the disk. The local infection can be both standardized and evaluated by determining the bacterial count on the disk. The antimicrobial efficacy of ceftizoxime was compared with other commercially available antibiotics administered in a single dose, 40 mg/kg subcutaneously, one hour after implantation of the disk. Using such a regimen ceftizoxime was found to be superior to a clindamycin-gentamicin combination and equal to or superior to cefoxitin in these models.

Animals↗

PubMed2003

Loss of protein phosphatase 2A expression correlates with phosphorylation of DP-1 and reversal of dysplasia through differentiation in a conditional mouse model of cancer progression.

A conditional mouse model of time-dependent dysplasia reversal demonstrated that reversal and differentiation of dysplastic salivary gland tissue at the 4-month reversible stage was characterized by the appearance of a phosphorylated slower mobility form of Differentiation Related Transcription Factor 1-polypeptide-1 that was correlated with cellular differentiation. The phosphorylated form of DP-1 was not found at the 7-month irreversible stage or in adenocarcinomas. At the 4-month reversible stage, protein phosphatase 2A expression was down-regulated coincident with loss of oncogene expression, whereas PP2A expression persisted at the 7-month irreversible stage. Results are consistent with the hypothesis that persistent PP2A expression prevented the appearance of the phosphorylated form of DP-1 required for cellular differentiation and reversal of dysplasia after loss of oncogene expression.

Adenocarcinoma↗

PubMed1998

Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model.

We have generated a transgenic mouse model in which female mice develop ductal mammary adenocarcinomas and male mice develop prostatic adenocarcinomas by using a transgene containing the hormone-responsive rat prostatic steroid binding protein 5' flanking region C3(1) fused to the simian virus 40 (SV40) large T antigen. We have identified some genetic alterations during mammary and prostate tumor progression: (i) p53 is functionally inactivated during mammary cancer development without p53 mutations; (ii) Alterations in apoptosis during mammary tumor progression are p53 and bcl-2 independent; (iii) Ha-ras mutations occur early in the development of prostate cancer. This unique animal model offers the opportunity to study multistep tumorigenesis in these organs.

Adenocarcinoma↗

PubMed2005

The use of three-dimensional ultrasound micro-imaging to monitor prostate tumor development in a transgenic prostate cancer mouse model.

Longitudinal studies of mouse cancer models required large cohorts since autopsy was the only reliable method to evaluate treatment efficacy. This paper reports the use of high-resolution three-dimensional ultrasound micro-imaging to monitor prostate tumor development in genetically engineered mice. Twenty-nine genetically engineered prostate cancer mice, including castrated and uncastrated mice, were imaged by three-dimensional ultrasound. Qualitative comparisons of three-dimensional ultrasound images with histology sections of prostate tumors demonstrate the ability of ultrasound to accurately depict the size and shape of malignant masses in live mice. The correlation coefficient of tumor diameter measurements performed in vivo with three-dimensional ultrasound and at autopsy was 0.997. Prospective tumor detection sensitivity and specificity were 91.7% and 100%. Representative exponential growth curves constructed via longitudinal ultrasound imaging indicated diameter doubling times from 10 to 37 days for four prostate tumors during an initial period of rapid progression. Three-dimensional ultrasound will likely become the micro-imaging modality most readily adopted for mouse pre-clinical trial studies.

Animals↗

PubMed1988

The hypoxic mouse model for screening cerebral protective agents: a re-examination.

The hypoxic mouse model, in which mice are subjected to an atmosphere of 5% O2 in nitrogen, has been used to screen anesthetics for possible cerebral protection by measuring their ability to prolong survival in mice exposed to hypoxia. Although prolonged survival time in this model is primarily due to a decreased cerebral metabolic rate produced by a specific anesthetic, results can also be influenced by body temperature, dose of anesthetic, and ventilatory or circulatory depression produced by the anesthetic. Using the hypoxic mouse model, the effects of thiopental in conjunction with changes in ambient temperature, changes in thiopental dose, and the presence or absence of nitrous oxide (N2O) were examined. Survival times were measured in eight groups of animals, either untreated animals or animals pretreated with 100 mg/kg thiopental intraperitoneally; exposed to hypoxia in the presence or absence of N2O; at ambient temperatures of either 25 degrees C or 35.5 degrees C. Survival times of seven additional groups of mice, either untreated or treated with doses of 50, 60, 70, 80, 90 or 120 mg/kg thiopental intraperitoneally, exposed to hypoxia in an ambient temperature of 35.5 degrees C were measured to determine a dose-response curve. At an ambient temperature of 35.5 degrees C in which the rectal temperature of both untreated and thiopental-treated animals was maintained near 36 degrees C, thiopental-treated animals did not survive any longer than the untreated animals. Exposure to N2O shortened survival times of both groups by approximately 20%.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗

PubMed2003

A transgenic mouse model for the detailed morphological study of astrocytes.

We have generated a transgenic mouse model in which astrocytes express an enhanced green fluorescent protein (EGFP) under the control of the mouse glial fibrillary acidic protein (GFAP) promoter. EGFP, which is characteristically found throughout the cell, was expressed in these animals even in astrocytic fine processes, and EGFP expressing cells demonstrated morphological characters of protoplasmic, fibrous, or reactive astrocytes. In contrast, GFAP immunoreactivity was found only in the perinuclear region and in the main processes. The transgenic mouse model therefore provides a valuable tool for the detailed morphological investigation of astrocytes.

Animals↗

PubMed2001

Tailoring cancer vaccines to the elderly: the importance of suitable mouse models.

The incidence of cancer has increased over the last decade, mainly due to an increase in the elderly population. Vaccine therapy for cancer is potentially less toxic than chemotherapy or radiation and could, therefore, be especially effective in older, more frail cancer patients. However, it has been shown that older individuals do not respond to vaccine therapy as well as younger adults. This has been attributed to T cell unresponsiveness, a phenomenon also observed in cancer patients per se. Activation of tumor-specific T cells by cancer vaccines might be an approach, especially suitable for elderly patients, to eradicate or to prevent recurrence of tumors after primary treatment. To tailor pre-clinical testing of vaccine therapies to the elderly, it is important to have mouse models in which tumors develop at equivalent time points in their life span, as in humans. Such models are currently not available. This progress report first summarizes the current knowledge of tumor-immunological parameters potentially involved in T cell unresponsiveness in relation to aging in mice and humans. Secondly, it reviews those cancer vaccines that are known for their potential to induce tumor-specific T cell responses. Thirdly, it discusses the usefulness of currently available mouse models for pre-clinical testing of cancer vaccines applicable to the elderly population. Finally, experimental approaches are proposed, as to how to develop mouse models that allow the induction of specific tumors at will at different ages, expressing tumor-specific antigens in an 'immune competent' environment. These mouse models may teach us how to overcome immune deficits in the elderly, thereby facilitating the development of effective and safe cancer vaccines.

Aged↗

PubMed1986

Studies on the genetic and cellular control of sensitivity to enterotoxins in the sealed adult mouse model.

A sealed adult mouse (SAM) model was developed for studies on the effects of cholera enterotoxin (CT). With this system, 38 strains of outbred, inbred, congenic, recombinant, and mutant mice were starved for 24 h, anorectally occluded with cyanoacrylamide ester glue, given CT per os, and sacrificed at 6 h. Fluid accumulation (FA) values were calculated as gut weight to body weight ratios. At a saturating dose of CT (24 micrograms per mouse), FA responses were found to be independent of body weight and gut length. It was found, using recombinant and congenic mice, that mice which possess the H-2k haplotype (homozygous or heterozygous) are 2.5 to 3 times less responsive to CT than animals with the H-2b haplotype. The allele(s) responsible for this affect is located near the K end of the H-2 complex. Inbred and congenic mice given CT intravenously exhibited the same (b = responder, k = nonresponder) pattern in terms of weight loss and death, thus indicating that the H-2 effect is not limited just to the small intestinal epithelium. Mice given sublethal doses of CT intravenously and challenged after conversion to SAM 14 days later showed an immune response inversely related to weight loss (i.e., b haplotypes lost 10 to 15% body weight, recovered, but were not protected against challenge; k haplotypes lost little or no weight but were protected). To examine the possibility of a cellular basis for control of innate responses to CT, responder C57BL/10 (B10) mice were irradiated with 950 rads and immediately reconstituted with bone marrow from (B10 X B10.BR)F1 (nonresponder) mice. The chimeras became nonresponsive to CT when challenged 5 weeks after reconstitution. Reconstituted B10 controls responded normally. Outbred and inbred nude athymic mice also were nonresponsive when compared with normal responder controls. These data demonstrate a genetic basis for resistance to CT and that response and nonresponse is mediated, at least in part, by cells derived from bone marrow.

Animals↗

PubMedDate not supplied

Cancer from the outside, aging from the inside: mouse models to study the consequences of defective nucleotide excision repair.

In recent years, mouse models have been generated to study the syndromes associated with a defect in nucleotide excision repair (NER). Thus, via conventional knockout gene targeting or by mimicking patient-specific alleles, mouse models for xeroderma pigmentosum (XP), Cockayne syndrome (CS) and photosensitive trichothiodystrophy (TTD) have been obtained. The generation of this series of mouse mutants allows in vivo investigation of some intriguing questions that have puzzled the field, such as the paradoxical absence of cancer development in TTD and CS despite their NER deficiencies, and the role of the ERCC1 gene in mitotic recombination and cross-link repair. Other interesting issues include the pathophysiology of the non-NER related clinical symptoms in TTD and CS patients and the proposed involvement of NER and transcription in the process of aging. This review will focus on data obtained thus far and discuss further utilization of the mouse mutants for unraveling some of the fascinating and medically relevant aspects associated with defects in NER and related processes.

Aging↗