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PubMed2005

Novel quantitative phenotypes of exercise training in mouse models.

Regular physical exercise has beneficial effects in many human disease states, including cardiovascular diseases, cancer, and depression. Exercise training of genetically modified mouse models may provide insight into the molecular mechanisms that underlie the beneficial effects of exercise. Presently, there is relatively little understanding of the normal physiology of mouse exercise. In this paper, we describe a novel computerized voluntary wheel-running system capable of recording and analyzing individual wheel rotations. Using this system, we demonstrate that C57BL/6 mice run considerable distances during the night in short bouts and at a preferred speed: the cruising speed. We find that the vast majority of running occurs around this cruising speed, which is close to the maximum speed at which the animal can run but is significantly higher than the average speeds recorded by simple digital odometers. We describe how these parameters vary with exercise training and demonstrate marked sex differences in the patterns of voluntary exercise. The results of this study have important implications for the design and interpretation of both voluntary and forced exercise experiments in mouse models. The novel parameters described provide more physiological quantitative measures of voluntary exercise activity and training and will extend the physiological utility of exercise training as a phenotyping tool in genetic mouse models.

Animals↗

PubMed2006

Plaques, tangles, and memory loss in mouse models of neurodegeneration.

Within the past decade, our understanding of the pathogenic mechanisms in Alzheimer's disease (AD) has dramatically advanced because of the development of transgenic mouse models that recapitulate the key pathological and behavioral phenotypes of the disease. These mouse models have allowed investigators to test detailed questions about how pathology develops and to evaluate potential therapeutic approaches that could slow down the development of this disease. In this review, we discuss the status of transgenic mouse models and review the complex relationship between pathology and behavior in the development of neuropathological syndromes in AD.

Alzheimer Disease↗

PubMed2005

A mouse model of ethanol dependent pancreatic fibrosis.

BACKGROUND AND AIMS: The majority of patients with chronic pancreatitis are alcoholics. Our goal was to develop a mouse model of alcohol dependent chronic pancreatitis. METHODS: Mice were fed either the non-alcohol containing Lieber-DeCarli diet or the Lieber-DeCarli diet containing 24% of calories as ethanol. After eight weeks and while on their respective diets, mice were subjected to repeated episodes of acute pancreatitis elicited by administration of caerulein. They were sacrificed 1, 3, and 5 weeks after the last dose of caerulein. Pancreatic morphology and collagen deposition were evaluated in samples stained with haematoxylin-eosin and Sirius red. Collagen content was quantitated by measuring OH-proline. Gene expression was determined by quantitative polymerase chain reaction. RESULTS: Both groups of mice gained weight at the same rate. Those receiving the alcohol containing diet had serum alcohol levels of approximately 100 mM. No histological or gene expression differences were found in mice that were not subjected to acute pancreatitis, regardless of their diet. Necrosis, Sirius red staining, OH-proline content, and expression of alpha-1 collagen I, alpha-smooth muscle actin, transforming growth factor beta1, and tissue inhibitor of metalloproteinase 1 were all increased in mice fed the alcohol containing diet and given caerulein compared with those fed the control diet and given caerulein. Matrix metalloproteinase 9 expression was transiently decreased in mice fed ethanol and given caerulein compared with the group given caerulein but not fed ethanol. CONCLUSION: We have developed a mouse model of alcohol dependent chronic pancreatic fibrosis. This mouse model may be useful in studies examining the effects of genetic manipulation on chronic pancreatitis.

Animals↗

PubMed1998

Induced mouse models of abnormal sphingolipid metabolism.

Only a limited number of genetic mouse models of abnormal sphingolipid metabolism are known to occur spontaneously. However, recent progress in the combined homologous recombination and embryonic stem cell technology allows inactivation of any genes of choice once they are cloned. Not only is it possible to generate mutant mouse lines that are equivalent to known human genetic disorders but genetic conditions unknown or highly unlikely to occur in humans, such as simultaneous inactivation of more than one gene, can also be created. Most of the human disorders due to genetic defects in sphingolipid catabolism have been duplicated in the mouse. With increasing activity in cloning of the enzymes involved in sphingolipid biosynthesis, genetic mouse models of abnormal sphingolipid biosynthesis are beginning to appear. These models have already provided invaluable insight into the metabolism and physiological functions of sphingolipids and are expected to be utilized extensively for evaluation of the pathogenesis and of treatment approaches of these genetic disorders.

Animals↗

PubMed2006

Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome.

The Ts65Dn mouse model of Down syndrome (DS) has an extra segment of chromosome (Chr.) 16 exhibits abnormal behavior, synaptic plasticity and altered function of several signaling molecules. We have further investigated signaling pathways that may be responsible for the impaired hippocampal plasticity in the Ts65Dn mouse. Here we report that calcium/calmodulin-dependent protein kinase II (CaMKII), phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase (ERK), protein kinase A (PKA) and protein kinase C (PKC), all of which have been shown to be involved in synaptic plasticity, are altered in the Ts65Dn hippocampus. We found that the phosphorylation of CaMKII and protein kinase Akt was increased, whereas ERK was decreased. Activities of PKA and PKC were decreased. Furthermore, abnormal PKC activity and an absence of the increase in Akt phosphorylation were demonstrated in the Ts65Dn hippocampus after high-frequency stimulation that induces long-term potentiation. Our findings suggest that abnormal synaptic plasticity in the Ts65Dn hippocampus is the result of compensatory alterations involving the glutamate receptor subunit GluR1 in either one or more of these signaling cascades caused by the expression of genes located on the extra segment of Chr. 16.

Animals↗

PubMed2001

Analysis of ubiquitination in vivo using a transgenic mouse model.

The primary pathway for the proteolytic destruction of cellular proteins is through ubiquitin-mediated targeting to the proteasome. This pathway is pivotal not only in the elimination of damaged or misfolded proteins but also in the temporal, developmental, or signal-mediated destruction of normal cellular substrates. The list of known substrates of the ubiquitin/proteasome pathway is long, but most substrates have been identified in yeast or, more recently, in cultured mammalian cells. It is likely that many mammalian substrates with developmental or disease relevance have yet to be identified because their ubiquitination occurs in tissue or organ systems that cannot be adequately modeled in vitro. We have developed a transgenic mouse model that will allow the isolation and identification of these substrates. The human UbC promoter was used to drive expression of a hexahistidine-tagged version of human ubiquitin in a variety of mouse tissues from early embryonic stages, as assessed by a green fluorescent protein marker. Cleavage of the fusion protein by endogenous enzymes produced epitope-tagged ubiquitin that was detected both in monomeric form and conjugated to cellular proteins. This mouse model should facilitate in the analysis of normal and disease-related ubiquitination events in vivo.

Animals↗

PubMed2006

Application of functional genomics to the chimeric mouse model of HCV infection: optimization of microarray protocols and genomics analysis.

BACKGROUND: Many model systems of human viral disease involve human-mouse chimeric tissue. One such system is the recently developed SCID-beige/Alb-uPA mouse model of hepatitis C virus (HCV) infection which involves a human-mouse chimeric liver. The use of functional genomics to study HCV infection in these chimeric tissues is complicated by the potential cross-hybridization of mouse mRNA on human oligonucleotide microarrays. To identify genes affected by mouse liver mRNA hybridization, mRNA from identical human liver samples labeled with either Cy3 or Cy5 was compared in the presence and absence of known amounts of mouse liver mRNA labeled in only one dye. RESULTS: The results indicate that hybridization of mouse mRNA to the corresponding human gene probe on Agilent Human 22 K oligonucleotide microarray does occur. The number of genes affected by such cross-hybridization was subsequently reduced to approximately 300 genes both by increasing the hybridization temperature and using liver samples which contain at least 80% human tissue. In addition, Real Time quantitative RT-PCR using human specific probes was shown to be a valid method to verify the expression level in human cells of known cross-hybridizing genes. CONCLUSION: The identification of genes affected by cross-hybridization of mouse liver RNA on human oligonucleotide microarrays makes it feasible to use functional genomics approaches to study the chimeric SCID-beige/Alb-uPA mouse model of HCV infection. This approach used to study cross-species hybridization on oligonucleotide microarrays can be adapted to other chimeric systems of viral disease to facilitate selective analysis of human gene expression.

Animals↗

PubMed2003

[Create the mouse model of severe acute pancreatitis induced by caerulein plus lipopolysaccharide and study on its pathogenesis].

To set up a nontraumatic and convenient mouse model of severe acute pancreatitis (SAP). Caerulein(Cn) was injected the mice intraperitonealy with lipopolysaccharide(LPS). Serum amylase and pancreas weight were measured in experiment. The pathological changes of pancreas and other organs were observed under light microscope. The ultrastructure of acini were observed under transmission electron microscope (TEM). Serum NO concentration were measured and the SOD and MDA in pancreas were examined. The results in Cn + LPS group were showed that serum amylase, NO concentration and pancreas weight were increased, SOD deduced and MDA increased. Severe edema, inflammation infiltration, necrosis and different extent of hemorrhage were showed. The acini were damaged severely. And the lesion of other organs were also happened. In Cn group, there were only pancreatic interstitial edema but no parenchmal necrosis or hemorrhage, and the other organs were normal. In LPS group, pancreas were almost normal and the organs besides pancreas were only showed light inflammation infiltration. The SAP mouse model induced by caerulein plus LPS has the same pathological characteristics of human SAP, which can be used in human SAP research. The unbalance of oxygen free radical release-elimination and oxidation-antioxidation mechanisms might be involved in the pathogenesis of mouse model of severe acute pancreatitis induced by intraperitoneal injection of caerulein plus LPS.

Acute Disease↗

PubMed2004

Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer.

PURPOSE: The RNA interference effect is an alternative to antisense DNA as an experimental method of down-regulating a specific target protein. Although the RNA interference effect, which is mediated by small interfering RNA (siRNA) or micro-RNA, has potential application to human therapy, the hydrodynamic method usually used for rapid administration of oligonucleotides is unsuitable for use in humans. In this study, we have investigated the antitumor activity of a synthetic siRNA, B717, which is sequence specific for the human bcl-2 oncogene, complexed with a novel cationic liposome, LIC-101. EXPERIMENTAL DESIGN: In a mouse model of liver metastasis, we administered B717/LIC-101 by bolus intravenous injection, adjusting the rate and volume of administration to what is feasible in human therapy. In a mouse model bearing prostate cancer in which the cells were inoculated under the skin, B717/LIC-101 was administered subcutaneously around the tumor. RESULTS: The B717/LIC-101 complex inhibited the expression of bcl-2 protein and the growth of tumor cell lines in vitro in a sequence-specific manner in the concentration range of 3 to 100 nmol/L. Furthermore, the complex had a strong antitumor activity when administered intravenously in the mouse model of liver metastasis. B717 (siRNA) was shown to be delivered to tumor cells in the mouse liver, but only when complexed with LIC-101. The complex also inhibited tumor cell growth in the mouse model bearing prostate cancer. CONCLUSIONS: By combining siRNA with our cationic liposome, we overcame the difficulty of administering siRNA to animals in ways that can be applied in human therapy. Although our siRNA/liposome complex is not yet in clinical trials, it is expected to provide a novel siRNA therapy for cancer patients.

Animals↗

PubMed2002

Immunization and immunotherapy for cancers involving infection by a human papillomavirus in a mouse model.

We describe a protocol for generating a potent cellular immune response against viral-infected cells, and demonstrate its efficacy and safety in a mouse model of human cancer associated with infection by a human papillomavirus (HPV). In the mouse model, the mouse tumor TC-1, which expresses the E7 oncoprotein from HPV-16, is used as a surrogate for human tumors infected with HPV-16. The antigen for the protocol is composed of the E7 oncoprotein conjugated to the Fc region of a mouse IgG1 Ig (E7-mFc). The mFc domain should bind to Fc receptors on dendritic cells, enhancing the processing and presentation of E7 peptides by dendritic cells to T cells, which mediate a cellular immune attack against tumors expressing E7. The E7-mFc antigen was encoded in a replication-incompetent adenoviral vector, called Ad(E7-mFc), for infection of the human kidney cell line 293. The infected 293 cells synthesize the E7-mFc antigen and also infectious Ad(E7-mFc) vector particles for approximately equal 2 days, until the cells lyse and the vector particles are released. To test the protocol for immunization against formation of a TC-1 tumor, the mice first were injected s.c. with 293 cells infected with Ad(E7-mFc), followed by two challenges with TC-1 cells. The immunized mice remained healthy and tumor-free for the 6-month duration of the experiment, and the autopsies showed no toxicity. In the control mice immunized with 293 cells infected with an adenoviral vector that does not encode the E7-mFc antigen, the TC-1 tumor grew continuously and the mice had to be killed within 1 month. To test the protocol for immunotherapy, the mice first were injected with TC-1 cells, followed by s.c. injections of 293 cells infected with Ad(E7-mFc). Tumor growth was prevented or strongly retarded in these mice, in contrast to the continuous tumor growth in the controls. These results suggest that the protocol could be adapted for immunization against human cancers associated with an HPV infection, notably cervical cancer, and for immunotherapy to prevent recurrence of a tumor after surgery.

Adenoviridae↗

PubMed2000

Early alterations in gene expression and cell morphology in a mouse model of Huntington's disease.

Several mouse models for Huntington's disease (HD) have been produced to date. Based on differences in strain, promoter, construct, and number of glutamines, these models have provided a broad spectrum of neurological symptoms, ranging from simple increases in aggressiveness with no signs of neuropathology, to tremors and seizures in absence of degeneration, to neurological symptoms in the presence of gliosis and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) positivity, and finally to selective striatal damage associated with electrophysiological and behavioral abnormalities. We decided to analyze the morphology of striatum and hippocampus from a mouse transgenic line obtained by microinjection of exon 1 from the HD gene after introduction of a very high number of CAG repeat units. We found a massive darkening and compacting of striatal and hippocampal neurons in affected mice, associated with a lower degree of more classical apoptotic cell condensation. We then explored whether this morphology could be explained with alterations in gene expression by hybridizing normal and affected total brain RNA to a panel of 588 known mouse cDNAs. We show that some genes are significantly and consistently up-regulated and that others are down-regulated in the affected brains. Here we discuss the possible significance of these alterations in neuronal morphology and gene expression.

Animals↗

PubMed1995

Evaluation of water-soluble pneumocandin analogs L-733560, L-705589, and L-731373 with mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.

The activities of the water-soluble pneumocandin derivatives L-733560, L-705589, and L-731373 were evaluated in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis and were compared with those of commercially available antifungal agents. Pneumocandins are inhibitors of 1,3-beta-D-glucan synthesis. In the aspergillosis model, L-733560 and L-705589 significantly prolonged the survival of DBA/2N mice challenged intravenously with Aspergillus fumigatus conidia. L-733560 and L-705589 exhibited efficacies comparable to that of amphotericin B (AMB) with 90% effective doses of 0.48, 0.12, and 0.36 mg/kg of body weight, respectively. Two mouse models of disseminated candidiasis were used to evaluate these compounds. In both models, mice were challenged intravenously with Candida albicans. In a C. albicans survival model with DBA/2N and CD-1 mice, the efficacy of L-733560 was comparable to that of AMB, while L-731373 and L-705589 were somewhat less active. In a previously described C. albicans target organ kidney assay, the pneumocandin analogs and AMB at doses of > or = 0.09 mg/kg were effective in sterilizing kidneys, while fluconazole and ketoconazole were considerably less active and did not sterilize kidneys when they were used at concentrations of < or = 100 mg/kg. Although orally administered L-733560 showed activity in both candidiasis models, its efficacy was reduced compared with that of parenterally administered drug. In a disseminated cryptococcosis mouse model that measures the number of CFU of Cryptococcus neoformans per gram of brain and spleen, L-733560 at 10 mg/kg was ineffective in reducing the counts in organs, while AMB at 0.31 mg/kg sterilized the organs. These results indicate that the pneumocandins may be beneficial as potent parenterally administered therapeutic agents for disseminated aspergillosis and candidiasis.

Animals↗

PubMed2002

Anti-inflammatory effect of cerivastatin in vascular injury independent of serum cholesterol and blood pressure lowering effects in mouse model.

OBJECTIVE: To observe the anti-inflammatory effect of cerivastatin in a mouse model of vascular injury and its cholesterol-lowering effect. METHODS: We developed a mouse model of vascular remodeling induced by polyethylene cuff placement and determined the anti-inflammatory effects of cerivastatin in wild mice. Cerivastatin was given by Alzet micro-osmotic minipumps implanted intraperitoneally at the same time as cuff placement at doses of 0.1 mg/kg, 0.5 mg/kg and 1 mg/kg per day, respectively for 2 weeks after cuff placement. The insufficient doses of Cerivastatin to lower serum cholesterol and systolic blood pressure through the neointimal formation and BrdU index were investigated in mouse femoral injury artery induced by cuff-placement. RESULTS: There was a little change in serum cholesterol by the treatment with cerivastatin, the cross-sectional area of intima of injured femoral artery was significantly increased, the neointima formation was significantly increased by the cuff-induced vascular injury at day 14. The neointimal formation and BrdU index were inhibited in the 1 mg/kg cerivastatin, but not in the 0.1 mg/kg and 0.5 mg/kg cerivastatin. Furthermore, 1 mg/kg of cerivastatin significantly inhibited the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) without lowering serum cholesterol. CONCLUSIONS: These results suggest that cerivastatin can inhibit vascular inflammation and the proliferation of vascular smooth muscle cells (VSMCs) through its lipid-lowering independent action. Such effects of cerivastatin may be an important mechanism, by which it prevents the development of atherosclerotic lesions.

Animals↗

PubMed2006

Antibody-mediated disease remission in the mouse model of lyme borreliosis.

In the mouse model of Lyme borreliosis, the host immune response during infection with Borrelia burgdorferi results in the remission of carditis and arthritis, as well as global reduction of spirochete numbers in tissues, without elimination of infection. These events were recapitulated by passive transfer of immune serum from infected immunocompetent mice or T-cell-deficient mice to severe combined immunodeficient (SCID) mice. Previous studies have shown that immune serum is reactive against arthritis-related protein (Arp) and that Arp antiserum induces arthritis remission. However, although immune serum from T-cell-deficient mice induced disease remission, it was not reactive against Arp, suggesting that antibody to another antigen may be responsible. T-cell-deficient mouse immune serum was reactive to decorin binding protein A (DbpA). Therefore, DbpA antiserum was tested to determine its ability to induce disease remission in SCID mice. Antisera to Arp or DbpA induced both carditis and arthritis remission but did not significantly reduce spirochete numbers in tissues, based upon quantitative flaB DNA analysis, nor did treatment affect RNA levels of several genes, including arp and dbpA. Immunohistochemical labeling of spirochetes in hearts and joints during disease remission induced by adoptive transfer of lymphocytes, passive transfer of immune serum, or passive transfer of DbpA antiserum revealed that such treatment resulted in elimination of spirochetes from heart base and synovium but not vascular walls, tendons, or ligaments. These results suggest that Arp and DbpA antibodies may be active as disease-resolving components in immune serum but antibody against other antigens may be involved in reductions of spirochetes in tissues.

Animals↗

PubMed2006

Metabolic consequences of lipodystrophy in mouse models.

PURPOSE OF REVIEW: Adipose tissue is a key player in metabolic homeostasis through its role as an energy depot and endocrine organ. The characterization of mouse models of lipodystrophy, in which adipose tissue development and function are impaired, has shed new light on the mechanisms by which adipose tissue dysregulation may contribute to conditions such as insulin resistance, fatty liver, and beta-cell toxicity. RECENT FINDINGS: Here we review recent findings from mouse models with genetic alterations leading to reduced adipose tissue mass. The metabolic consequences depend on the basis for the adipose tissue reduction, and we classify mouse models into three categories based on whether they confer (1) lipoatrophy accompanied by insulin resistance, (2) reduced adipose tissue storage associated with enhanced energy expenditure, or (3) both lipoatrophic and energetic effects. SUMMARY: Reductions in the capacity of adipose tissue to store triglycerides or to secrete adipokine hormones lead to altered lipid metabolism and insulin resistance. In contrast, depletion of fat stores by virtue of enhanced energy metabolism does not produce undesirable metabolic effects. However, enhanced energy metabolism cannot overcome the deleterious effects of impaired adipokine production, as revealed by studies of models with both lipoatrophic and energetic effects.

Adipose Tissue↗

PubMed2000

Insights from mouse models of colitis.

Emerging studies using mouse models of experimental colitis are defining the nature of the immunological disturbances that initiate inflammation and destruction of the intestine. A better understanding of disease-promoting and -suppressing CD4+ T cells is providing insight into the mechanisms controlling immune responses within the intestinal compartment. Moreover, a role for distinct T cell populations, including intraepithelial gammadelta T cells, in maintaining the physical integrity of the intestine was suggested by recent studies. Cytokine gene-knockout mice and anti-cytokine treatments remain important tools to define the pro- and anti-inflammatory functions of cytokines. These advances are fostering the design and evaluation of new therapeutic approaches that may eventually be applied to treat human inflammatory bowel disease.

Animals↗

PubMed2004

Comparing adiposity profiles in three mouse models with altered GH signaling.

Three mouse lines with altered growth hormone (GH) signaling were used to study GH's role in adiposity. Dwarf GH receptor knockout mice (GHR -/-) and bovine GH antagonist expressing mice (GHA) had an increased percent body fat with most of the excess fat mass accumulating in the subcutaneous region. Giant bovine GH expressing mice (bGH) had a reduced percent body fat. Only GHA mice consumed significantly more food per body weight. Serum leptin levels were significantly increased in GHA mice and decreased in bGH mice but unchanged in the GHR -/- mice. Interestingly, serum adiponectin levels were significantly increased in the GHR -/- and GHA lines but decreased in bGH mice. These data suggest that suppression or absence of GH action and enhanced GH action indeed have opposite metabolic effects in terms of adiposity. Interestingly, adiponectin levels were positively correlated with previously reported insulin sensitivity of these mice, but also positively correlated with adiposity, which is contrary to findings in other mouse models. Thus, adiponectin levels were negatively correlated with GH function suggesting a role for adiponectin in GH-induced insulin resistance.

Adiponectin↗

PubMed2002

Induction of ovarian cancer by defined multiple genetic changes in a mouse model system.

We have developed a mouse model for ovarian carcinoma by using an avian retroviral gene delivery technique for the introduction of multiple genes into somatic ovarian cells of adult mice. Ovarian cells from transgenic mice engineered to express the gene encoding the avian receptor TVA were efficiently infected in vitro with multiple vectors carrying coding sequences for oncogenes and marker genes. When target cells were derived from TVA transgenic mice deficient for p53, the addition of any two of the oncogenes c-myc, K-ras, and Akt were sufficient to induce ovarian tumor formation when infected cells were injected at subcutaneous, intraperitoneal, or ovarian sites. We demonstrated that the ovarian surface epithelium is the precursor tissue for these ovarian carcinomas, and that introduction of oncogenes causes phenotypic changes in the ovarian surface epithelial cells. The induced ovarian tumors in mice resembled human ovarian carcinomas in their rapid progression and intraperitoneal metastatic spread.

Actins↗