Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mouse Model”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 415 records · Page 23Linked to original sources
PubMed2006

Short synthetic endostatin peptides inhibit endothelial migration in vitro and endometriosis in a mouse model.

OBJECTIVE: To determine the active peptide regions inside the angiogenesis inhibitor endostatin that can inhibit endothelial migration in vitro and also inhibit endometriosis in a mouse model. DESIGN: Pharmacologic intervention in a surgically induced mouse model of endometriosis and endothelial migration assay. SETTING: Animal research and laboratory facility. SUBJECT(S): Eight-week-old, female C57BL/6 mice and human microvascular endothelial cells. INTERVENTION(S): Eight overlapping synthetic peptides were tested for inhibitory potential on endothelial migration in vitro. The peptides with significant activity then were given for 4 weeks to mice after implantation of autologous endometrium. MAIN OUTCOME MEASURE(S): Inhibition of vascular endothelial growth factor-induced endothelial migration for in vitro studies. In vivo studies examined the growth rate of endometriotic lesions after 4 weeks of treatment, as well as the effect on estrous cycling and ovulation as assessed by corpus luteum formation. RESULT(S): The N-terminal mP-1 peptide and the internal mP-6 peptide inhibited endothelial migration in a dose-dependent manner. Additionally, both synthetic peptides suppressed growth of endometriotic lesions significantly in vivo. However, estrous cycling and corpus luteum formation were normal in both groups. CONCLUSION(S): Short endostatin fragments may be promising as a new, nontoxic therapeutic strategy for the treatment of endometriosis without inhibition of normal estrous cycles.

Amino Acid Sequence↗
PubMed2006

Using genetically engineered mouse models of cancer to aid drug development: an industry perspective.

Recent developments in the generation and characterization of genetically engineered mouse models of human cancer have resulted in notable improvements in these models as platforms for preclinical target validation and experimental therapeutics. In this review, we enumerate the criteria used to assess the accuracy of various models with respect to human disease and provide some examples of their prognostic and therapeutic utility, focusing on models for cancers that affect the largest populations. Technological advancements that allow greater exploitation of genetically engineered mouse models, such as RNA interference in vivo, are described in the context of target and drug validation. Finally, this review discusses stratagems for, and obstacles to, the application of these models in the drug development process.

Algorithms↗
PubMed2005

Hepatic gene expression changes in mouse models with liver-specific deletion or global suppression of the NADPH-cytochrome P450 reductase gene. Mechanistic implications for the regulation of microsomal cytochrome P450 and the fatty liver phenotype.

NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferator-activated receptor-alpha by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid translocase (Cd36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (Cpt1a) and acyl-CoA synthetase long chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis and an altered fatty acid profile observed in liver-Cpr-null mice.

Animals↗
PubMed2003

Relationship between the immune response and protection conferred by new designed inactivated vaccines against ovine enzootic abortion in a mouse model.

Chlamydophila abortus is a gram-negative obligate intracellular bacterium and the etiological agent of ovine enzootic abortion (OEA), an economically important disease in many countries. Inactivated vaccines have been reported to induce immunity in ewes and they have been used for many years. However, some outbreaks have been reported in correctly vaccinated flocks, so it is clear that new vaccines are necessary to address adequate protection and to avoid the shedding of the microorganism. This idea lead us to design inactivated vaccines, in a previously established mouse model, evaluating different inactivation procedures and new adjuvants. To assess the protection conferred, the results were analyzed on the basis of clinical signs and the isolation of C. abortus from spleen. These findings were correlated with the immune response induced by the vaccines, as determined by the production of C. abortus-specific IFN-gamma and IL-4 from splenocyte cultures and the detection of IgG isotypes in serum. BEI was found to be the best C. abortus-inactivation procedure. The inactivated vaccines adjuvated with QS-21 (QS) or Montanide 773 (M7) induced the best protection both against homologous and heterologous challenge, with an adequate (Th1-like) immune response. Finally, these selected vaccines were evaluated in a pregnant mouse model, in which they were seen to confer good protection and to avoid the C. abortus persistence in uterus after delivery. With these results, this mouse model could be considered as an adequate tool for selecting and optimizing effective vaccines against OEA.

Abortion, Veterinary↗
PubMed2006

A new mouse model for intraportal islet transplantation with limited hepatic lobe as a graft site.

Intraportal site is the standard for grafting in clinical islet transplantation. In the mouse model, the whole liver has been used as the grafting site to mimic clinical islet transplantation. However, this model lacks the potency to directly assess the contribution of the islet graft to diabetes control. Only demonstrating the immediate recurrence of diabetes in a surviving recipient after the removal of the islet graft can validate this assessment. In this study, we develop a mouse model of intraportal islet transplantation equipped with the potency of this assessment by injecting islets selectively into the right hepatic lobe under temporal clamp of the left portal vein. The mouse of this model survives after the right hepatectomy by which the islet graft is removed. This model can be applied to investigate both the specific graft-recipient interaction in the liver and the islet graft contribution to the control of diabetes.

Animals↗
PubMed1996

Development and applications of the SCID-hu mouse model.

The SCID-hu mouse was designed to serve as a preclinical model for the analysis of human physiology and pathophysiology. In distinction to other immunodeficient mouse models, SCID-hu mice are made upon implantation of intact human organ systems rather than dispersed cell populations. Two constructs, the SCID-hu Thy/Liv and the SCID-hu Bone models, have been developed to reproduce the differentiation and function of human hematopoietic progenitor cells within the human thymus and bone marrow microenvironments, respectively. This review focuses on several applications of these models: definition of multilineage and lineage-restricted human hematopoietic progenitor cells and evaluation of HIV disease and its treatment.

Animals↗
PubMed2005

Mouse models of human neurodegenerative disorders: requirements for medication development.

Central nervous system diseases constitute a major target for drug development. Transgenic mouse models, in which genes identified in familial forms of human brain diseases are expressed in mouse neurons and glia, offer opportunities to detect and follow pathologic progression and provide potential biomarkers by which to assess therapeutic interventions. Evidence for Alzheimer disease suggests some starting requirements for the experimental data that could enhance the likelihood of developing medications in these mouse models that would also be effective in humans.

Alzheimer Disease↗
PubMed1998

Differential effects of estrogen and prolactin on autoimmune disease in the NZB/NZW F1 mouse model of systemic lupus erythematosus.

Estrogen and prolactin have been shown to modulate autoimmunity in the NZB/NZW F1 (B/W) mouse model of systemic lupus erythematosus (SLE). However, estrogen stimulates prolactin secretion. The goal of this study was to examine differential effects of estrogen and prolactin in the female B/W mouse model of SLE. B/W females were manipulated to create combinations of low and high concentrations of serum estrogen and prolactin. Hyperprolactinemic mice with either low or high serum estrogen levels had accelerated development of albuminuria at 24 and 32 weeks of age compared to normal and hypoprolatinemic mice. High estrogen/high prolactin mice also had a higher percentage of anti-DNA antibodies compared to mice in the low estrogen/low prolactin and the high estrogen/low prolactin groups. IgG levels were not significantly different between groups. Mean survival was shortest in the high estrogen/high prolactin group (34+/-1.0 weeks) and longest in the high estrogen/low prolactin group (42+/-1.2 weeks; P < 0.05). High levels of serum estrogen were associated with depressed in vitro lymphoproliferation and IL-2 production. This study suggests that high prolactin levels in either high or low serum estrogen states are associated with accelerated autoimmunity in the B/W mouse. This study further demonstrates that high estrogen levels do not accelerate murine SLE when the prolactin-stimulating property of estrogen is suppressed by bromocriptine. Further investigation of hormonal interactions in autoimmunity will provide a better understanding of hormonal immunoregulation and, perhaps, lead to improved clinical application of hormonal immunomodulation.

Animals↗
PubMedDate not supplied

Sleep-wake states in transgenic mouse models overexpressing the human beta-amyloid precursor protein.

Studies testing the amyloid hypothesis and recent advances in mouse molecular genetic technologies have played a critical role in improving our understanding of Alzheimer's disease (AD). Mouse models of AD currently available show only some of the characteristic neuropathology in human AD. Studies have demonstrated, however, that these models are excellent tools for characterizing different aspects of the molecular pathology of AD and the neurobiological basis for the clinical heterogeneity in AD. The present discussion focuses on behavioral and physiological data obtained in transgenic (Tg) mice overexpressing the mutant human beta-amyloid precursor protein (hbetaAPP). This mouse model exhibits memory and neurophysiological deficits at ages preceding amyloid-beta-peptide (Abeta) plaque formation that worsened with age and Abeta plaque formation. In spite of these findings, very little emphasis has been placed on characterizing the neurobiological basis of the diverse neuropsychiatric symptoms that are also observed in AD, including sleep disturbances. Taking into consideration the relationship between memory processes and sleep, the use of animal models of AD as a preclinical bioassay has the potential to characterize the neural substrates mediating clinical manifestations of AD, such as sleep-wake states, and contribute to the development of treatments for early stages of AD.

Alzheimer Disease↗
PubMed2005

Mouse models of resuscitated shock.

Studies of sepsis in humans are difficult because the seriousness of the disease mandates immediate intervention and because the heterogeneity of patient presentations imposes substantial limitations on clinical trials. Thus, animal models have been used extensively to explore the pathogenesis of sepsis and to generate preclinical data for therapeutic interventions. Translation of findings in these models into therapeutic strategies has been difficult, in part because of limitations in preclinical models and in part to imperfect understanding of the pathophysiology of sepsis. It is important to use an animal model that reproduces the relevant physiologic parameters present in patients with septic shock. Mouse models are particularly useful for the dissection of molecular mechanisms of disease because of the proliferation of transgenic strains. We have developed a murine model of sepsis with fluid resuscitation and antibiotic treatment that reproduces the timing and degree of mortality seen in patients with septic shock. Using continuous micromanometric pressure monitoring and assessment of hemodynamics by echocardiography, we have shown that this model reproduces the hyperdynamic state with hypotension seen in clinical sepsis. The use of transgenic technology in appropriate murine models is exciting because of its potential to permit significant strides in our understanding of the molecular mechanisms of sepsis, multiple organ system failure, and other diseases. The use of reproducible and clinically relevant mouse models of shock is essential for delineation of pathogenetic mechanisms and for initial testing of potential therapeutic strategies.

Animals↗
PubMed2005

Non-invasive imaging of a transgenic mouse model using a prostate-specific two-step transcriptional amplification strategy.

Non-invasive assessment of transgenic animals using bioluminescence imaging offers a rapid means of evaluating disease progression in animal models of disease. One of the challenges in the field is to develop models with robust expression to image repetitively live intact animals through solid tissues. The prostate-specific antigen (PSA) promoter is an attractive model for studying gene regulation due to its hormonal response and tissue-specificity permitting us to measure signaling events that occur within the native tissues. The use of the GAL4-VP16 activator offers a powerful means to augment gene expression levels driven by a weak promoter. We have used a two-step transcriptional amplification (TSTA) system to develop a transgenic mouse model to investigate the tissue-specificity and developmental regulation of firefly luciferase (fl) gene expression in living mice using bioluminescence imaging. We employed an enhanced prostate-specific promoter to drive the yeast transcriptional activator, GAL4-VP16 (effector). The reporter construct carries five Gal4 binding sites upstream of the fl gene. We generated a transgenic mouse model using a single vector carrying the effector and reporter constructs. The transgenic mice show prostate-specific expression as early as three weeks of age. The bioluminescence signal in the prostate is significantly higher than in other organs. We also demonstrate that blocking androgen availability can downregulate the fl expression in the prostate. The transgenic mice display normal physical characteristics and developmental behavior, indicating that the high level of GAL4 driven expression is well tolerated. These findings suggest that the GAL4-VP16 transactivator can be used to amplify reporter gene expression from a relatively weak promoter in a transgenic mouse model. The transgenic TSTA model in conjunction with other transgenic cancer models should also help to detect and track malignancies. The strategies developed will be useful for transgenic research in general by allowing for amplified tissue specific gene expression.

Animals↗
PubMed2003

Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma.

Phage display was used to identify homing peptides for blood vessels in a mouse model of HPV16-induced epidermal carcinogenesis. One peptide, CSRPRRSEC, recognized the neovasculature in dysplastic skin but not in carcinomas. Two other peptides, with the sequences CGKRK and CDTRL, preferentially homed to neovasculature in tumors and, to a lesser extent, premalignant dysplasias. The peptides did not home to vessels in normal skin, other normal organs, or the stages in pancreatic islet carcinogenesis in another mouse model. The CGKRK peptide may recognize heparan sulfates in tumor vessels. The dysplasia-homing peptide is identical to a loop in kallikrein-9 and may bind a kallikrein inhibitor or substrate. Thus, characteristics of the angiogenic vasculature distinguish premalignant and malignant stages of skin tumorigenesis.

Animals↗
PubMed1999

Mouse models of spike-wave epilepsy.

The mouse is a well-established model for human genetic disorders. An increasing number of single-gene human diseases are being elucidated through the use of mouse models. Recently genes for three of the six well-characterised single locus models for human spike-wave epilepsy have been isolated and published. The tottering mouse has been shown to be due to mutations in the gene encoding the high voltage-activated alpha1A calcium channel subunit. The lethargic mouse has been shown to be due to mutations in the gene encoding another calcium channel subunit, beta4. The slow-wave epilepsy mouse phenotype is the result of loss of function of the ubiquitous sodium hydrogen exchanger NHEI. These genes and the pathways they are involved in are now candidates for human spike-wave epilepsy. The six mouse models and those genes underlying the spike-wave phenotype are discussed in conjunction with how these mutations were discovered and how they may give rise to the seizure phenotypes. Several nonepilepsy human neurologic disorders have been shown to be allelic with the tottering mouse. The question this raises as to the validity of these models for human spike-wave epilepsy is considered. Finally, the effect these discoveries will have on the understanding and treatment of human spike-wave epilepsy are discussed.

Animals↗
PubMed2005

Inflammatory responses in a new mouse model of prolonged hepatic cold ischemia followed by arterialized orthotopic liver transplantation.

The current models of liver ischemia/reperfusion injury (IRI) in mice are largely limited to a warm ischemic component. To investigate the mechanism of hepatic "cold" IRI, we developed and validated a new mouse model of prolonged cold preservation followed by syngeneic orthotopic liver transplantation (OLT). Two hundred and forty-three OLTs with or without rearterialization and preservation in University of Wisconsin solution at 4 degrees C were performed in Balb/c mice. The 14-day survivals in the nonarterialized OLT groups were 92% (11/12), 82% (9/11), and 8% (1/12) after 1-hour, 6-hour and 24-hour preservation, respectively. In contrast, hepatic artery reconstruction after 1-hour, 6-hour, and 24-hour preservation improved the outcome as evidenced by 2-week survival of 100% (12/12), 100% (10/10), and 33% (4/12), respectively, and diminished hepatocellular damage (serum alanine aminotransferase /histology). Moreover, 24-hour (but not 1-h) cold preservation of rearterialized OLTs increased hepatic CD4+ T-cell infiltration and proinflammatory cytokine (tumor necrosis factor-alpha, interleukin 2, interferon-gamma) production, as well as enhanced local apoptosis, and Toll-like receptor 4/caspase 3 expression. These cardinal features of hepatic IRI validate the model. In conclusion, we have developed and validated a new mouse model of IRI in which hepatic artery reconstruction was mandatory for long-term animal survival after prolonged (24-h) OLT preservation. With the availability of genetically manipulated mouse strains, this model should provide important insights into the mechanism of antigen-independent hepatic IRI and help design much needed refined therapeutic means to combat hepatic IRI in the clinics.

Adenosine↗
PubMed2005

Generation and characterization of a transgenic mouse model with hepatic expression of human CYP2A6.

The aim of this study was to prepare and characterize a transgenic mouse model in which CYP2A6, a human P450 enzyme, is expressed specifically in the liver. CYP2A6, which is mainly expressed in human liver, is active toward many xenobiotics. Our transgene construct contained the mouse transthyretin promoter/enhancer, a full-length CYP2A6 cDNA, and a downstream neomycin-resistance gene for positive selection in embryonic stem cells. Hepatic expression of the CYP2A6 transgene was demonstrated by immunoblotting, whereas tissue specificity of CYP2A6 expression was confirmed by RNA-PCR. The transgenic mouse was further characterized after being backcrossed to the B6 strain for six generations. Hepatic microsomes from homozygous transgenic mice had activities significantly higher than those of B6 mice toward coumarin. The in vivo activity of transgenic CYP2A6 was also determined. Systemic clearance of coumarin was significantly higher in the transgenic mice than in B6 controls, consistent with the predicted role of CYP2A6 as the major coumarin hydroxylase in human liver. The CYP2A6-transgenic mouse model should be valuable for studying the in vivo function of this polymorphic human enzyme in drug metabolism and chemical toxicity.

Animals↗
PubMed1992

Interactions between Trichomonas vaginalis and vaginal flora in a mouse model.

To study the role of vaginal flora and pH in the pathogenesis of Trichomonas vaginalis, an intravaginal mouse model of infection was established. By employing this model, the vaginal flora and pH of mice could be monitored for changes caused by the parasite. As a baseline, the endemic vaginal flora of BALB/c mice was examined first and found to consist mainly of Staphylococcus aureus and Enterococcus species (32-76%). Lactobacilli and enteric bacilli were moderate (16-32%) in their frequency of isolation, and the prevalence of both anaerobic species and coagulase-negative staphylococci was low (4-16%). Vaginal pH was recorded at 6.5 +/- 0.3. Estrogenization, which was required for a sustained T. vaginalis infection, did not significantly alter vaginal flora; however, a slight rise in the number of bacterial species isolated per mouse and a drop in vaginal pH (6.2 +/- 0.5) were observed. Trichomonas vaginalis-infected mice did not appear to show significant changes in vaginal flora although vaginal pH was slightly increased. This mouse model could have applications in both immunologic and pathogenic studies of T. vaginalis and, with further modifications, aid in the study of protist-bacterial interactions.

Animals↗
PubMed2004

Osteogenic differentiation of recombinant adeno-associated virus 2-transduced murine mesenchymal stem cells and development of an immunocompetent mouse model for ex vivo osteoporosis gene therapy.

Gene therapy for osteopenic conditions including osteoporosis is a potential alternative to pharmacotherapy for cost effectiveness, long-term viability, and the ability to enhance bone mass by anabolic approaches. Increased understanding of mesenchymal stem cell (MSC) lineage differentiation during osteogenesis, and of the molecular pathways involved in bone cell production, provides an opportunity for the advancement of gene therapy approaches for osteopenic conditions. The potential of MSCs in osteoblast differentiation and the relative ease of MSC isolation and culturing offer a promising resource for the development of ex vivo gene therapy for bone defects. In an effort to develop ex vivo gene therapy for osteoporosis, we used gene-modified MSCs in a preclinical mouse model to determine the efficiency of transduction of murine MSCs by recombinant adeno-associated virus 2 (AAV) vectors carrying reporter genes and determined their osteogenic potential after recombinant AAV-mediated expression of bone morphogenic protein 2, known to induce osteoblast differentiation. Although surgical ovariectomy is believed to induce progressive bone loss in mouse models, similar to an osteoporosis-like phenotype in humans, several factors, including hormonal alteration and dietary habits, significantly affect both the onset and progression of the disease. Thus, in the present study, we determined the influence of these factors and developed an immunocompetent mouse model of osteoporosis with degenerative bone loss as in the human pathology.

Alkaline Phosphatase↗
PubMed2005

Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which results from selective loss of upper and lower motor neurons. Mouse models of ALS, such as one carrying the G93A mutant of the human Cu-Zn superoxide dismutase gene[SOD1(G93A)], develop motor neuron pathology and clinical symptoms similar to those observed in ALS patients. There is compelling evidence that both direct and indirect glutamate toxicity contribute to the pathogenesis of motor neuron degeneration. However, the therapeutic effect of various glutamate receptor antagonists has not been clearly demonstrated. Memantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro and in animal models of neurodegenerative diseases. In the current study, we have examined the therapeutic efficacy of memantine in an ALS mouse model carrying a high copy number of SOD1(G93A). Memantine treatment significantly delayed the disease progression and increased the life span of SOD1(G93A) mice, from 121.4 +/- 5.5 to 129.7 +/- 4.5 days (P = 0.032). Furthermore, NMDA receptor subunits were reliably detected in the spinal cord of SOD1(G93A) mice and their expression levels were similar to those in the wild-type littermate control. Therefore, the neuroprotective effect of memantine in SOD1(G93A) mice is most probably due to the inhibition of spinal cord NMDA receptors. In view of the long-term usage of memantine for dementia patients, with excellent tolerance and safety, these data suggest that memantine may be used in ALS patients alone or in combination with other therapies to prolong survival.

Amyotrophic Lateral Sclerosis↗