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At least 667 records · Page 37Linked to original sources
PubMed2002

Molecular biological approaches to neurological disorders including knockout and transgenic mouse models.

Advances of molecular biology have provided a great variety of new approaches to research on human disorders. This article gives an outline of molecular biological approaches to analysis of neurological disorders such as giant cell glioblastoma (GGBM) and amyotrophic lateral sclerosis (ALS), and their respective animal models: p53 knockout mice for GGBM and mutant superoxide dismutase-1 transgenic mice for ALS. Genomic DNA extracted from fresh-frozen tissue is examined by Southern blotting for screening mutations in a certain gene. Polymerase chain reaction (PCR) products of a gene in genomic DNA are examined by single-stranded conformation polymorphism, sequencing and agarose gel electrophoresis for identifying mutations, and for preparing and evaluating DNA probes used in Southern blotting and DNA in situ hybridization (ISH). Total RNA from tissue is examined by northern blotting for quantifying and verifying a certain mRNA. Reverse transcription-PCR products of a certain mRNA in total RNA are examined by sequencing and agarose gel electrophoresis for preparing and evaluating cDNA probes used in northern blotting and mRNA ISH. Tissue total protein is immunoblotted for quantifying and verifying a certain protein, and for evaluating the specificity of antibodies used in western blotting and immunohistochemistry. Immunoprecipitates are immunoblotted for evaluating a profile of protein or other substances. Enzyme-linked immunosorbent assay is used for measuring tissue concentration of protein or other substances, and for determining titers of specific antibodies. By these procedures, chronological analysis of animal models for human diseases contribute to elucidating pathogenic mechanisms and exploiting new therapies. Noticing both the similarity and difference between human and animal disorders will help understand the nature of disease.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Tyrosine kinase signalling in breast cancer: tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer.

The ability of growth factors and their cognate receptors to induce mammary epithelial proliferation and differentiation is dependent on their ability to activate a number of specific signal transduction pathways. Aberrant expression of specific receptor tyrosine kinases (RTKs) has been implicated in the genesis of a significant proportion of sporadic human breast cancers. Indeed, mammary epithelial expression of activated RTKs such as ErbB2/neu in transgenic mice has resulted in the efficient induction of metastatic mammary tumours. Although it is clear from these studies that activation these growth factor receptor signalling cascades are directly involved in mammary tumour progression, the precise interaction of each of these signalling pathways in mammary tumourigenesis and metastasis remains to be elucidated. The present review focuses on the role of several specific signalling pathways that have been implicated as important components in RTK-mediated signal transduction. In particular, it focuses on two well characterized transgenic breast cancer models that carry the polyomavirus middle T(PyV mT) and neu oncogenes.

Animals↗
PubMed2004

Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer.

BACKGROUND/AIMS: Co-expression of c-Myc and TGF-alpha in the mouse liver accelerates hepatocarcinogenesis and enhances DNA damage due to chronic oxidative stress. Dietary supplementation with vitamin E (VE) inhibits hepatocarcinogenesis and reduces chromosomal alterations in the same mice. Here we investigated the sources of reactive oxygen species (ROS) production in c-Myc/TGF-alpha transgenic mice. METHODS: Inducible nitric oxide synthase (iNOS) and NADPH oxidase levels were determined in c-Myc, TGF-alpha and c-Myc/TGF-alpha mice by RT-PCR, western blot analysis and immunohistochemistry. RESULTS: iNOS and nitrotyrosines levels were higher in the three transgenic lines when compared with wild-type mice. Preneoplastic and neoplastic lesions from c-Myc, TGF-alpha and c-Myc/TGF-alpha transgenic mice displayed upregulation of NADPH oxidase subunits p47-, 67-phox, Rac1, HSP 70, and HO-1. Importantly, dietary supplementation with vitamin E abolished iNOS expression, lowered nitrotyrosines, p47-, p67-phox, and Rac1 levels, and suppressed HSP 70 and HO-1 proteins in c-Myc/TGF-alpha livers. CONCLUSIONS: The results suggest that iNOS and NADPH oxidase are involved in ROS generation during c-Myc/TGF-alpha hepatocarcinogenesis and are inhibited by VE treatment. The data provide additional evidence for the potential use of VE in treatment of chronic liver diseases and HCC prevention.

Animals↗
PubMed2006

Human apoB overexpression and a high-cholesterol diet differently modify the brain APP metabolism in the transgenic mouse model of atherosclerosis.

Epidemiological and biochemical data suggest a link between the cholesterol metabolism, the amyloid precursor protein (APP) processing and the increased cerebral beta-amyloid (Abeta) deposition in Alzheimer's disease (AD). The individual and combined effects of a high-cholesterol (HC) diet and the overexpression of the human apoB-100 gene were therefore examined on the cerebral expression and processing of APP in homozygous apoB-100 transgenic mice [Tg (apoB(+/+))], a validated model of atherosclerosis. When fed with 2% cholesterol for 17 weeks, only the wild-type mice exhibited significantly increased APP695 (123%) and APP770 (138%) mRNA levels in the cortex. The HC diet-induced hypercholesterolemia significantly increased the APP isoform levels in the membrane-bound fraction, not only in the wild-type animals (114%), but also in the Tg apoB(+/+) group (171%). The overexpression of human apoB-100 gene by the liver alone reduced the brain APP isoform levels in the membrane-bound fraction (78%), whereas the levels were increased by the combined effect of HC and the overexpression of the human apoB-100 gene (134%). The protein kinase C and beta-secretase protein levels were not altered by the individual or combined effects of these two factors. Our data indicate that the two atherogenic factors, the HC diet and the overexpression of the human apoB-100 gene by the liver, could exert different effects on the processing and expression of APP in the mice brain.

Amyloid Precursor Protein Secretases↗
PubMed2006

Selective gene transfer to T lymphocytes using coreceptor-specific [MLV(HIV)] pseudotype vectors in a transgenic mouse model.

The coreceptor usage of HIV-1 envelope proteins (Env) is mainly dependent on a defined variable region within the V3-loop of Env. Thus, retroviral vectors derived from murine leukemia virus (MLV), which have been pseudotyped with HIV-1 envelope proteins holding different V3-loops, enable selective gene delivery into either CXCR4 or CCR5 positive cultured cells. Here, we tested the distribution of CD4/CCR5-tropic [MLV(HIV)]-pseudotype vectors in transgenic mice expressing CD4 and either CXCR4 or CCR5 of human origin. The specificity of gene transfer was analyzed by ex vivo transduction of spleen cells as well as after i.v. or i.p. injection of transgenic mice. Expression of the transferred marker gene EGFP and vector sequences could be detected exclusively in lymphocytes expressing (hu)CD4 and (hu)CCR5, whereas MLV vectors pseudotyped with the VSV-G envelope glycoprotein mediated gene transfer in mice of all genotypes investigated. These data demonstrated that cell-specific gene delivery via [MLV(HIV)]-pseudotyped vectors, as previously shown for cultured cells, is also achievable in vivo.

Animals↗
PubMed1999

Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Dominant mutations in the copper/zinc superoxide dismutase (SOD1) gene have been observed in 15-20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism by which SOD1 mutations result in motor neuron degeneration in FALS mice partly involves oxidative damage and an increased peroxidase activity of the mutant SOD1. A new therapeutic approach designed to eliminate the substrate of this peroxidase activity was examined in two lines of transgenic mice expressing the FALS-linked mutation glycine to alanine (G93A). We investigated the ability of putrescine-modified catalase (PUT-CAT), an antioxidant enzyme that removes hydrogen peroxide and has increased permeability at the blood-brain barrier, to modify the time course of the SOD1 mutation-induced motor neuron disease in these FALS mice. Continuous, subcutaneous administration of PUT-CAT significantly delayed the age at which onset of clinical disease occurred (indicated by loss of splay and/or tremors of hindlimbs) in a high-expressor line of FALS transgenic mice. Intraperitoneal injection of PUT-CAT given two times per week also significantly delayed the onset of clinical disease in a low-expressor line of FALS mice. PUT-CAT also significantly delayed the age at which clinical weakness developed (quantified by measuring the shortening of stride length) in both lines of FALS animals. No significant changes were observed in the survival times of the high-expressor FALS mice in any of the treatment groups. However, a trend toward a prolongation of survival was observed in the PUT-CAT-treated low-expressor FALS mice. These results support the role of free radical-mediated damage in the cascade of events leading to motor neurodegeneration in FALS and indicate that PUT-CAT interacts with a critical step in this cascade to delay the onset of clinical disease as well as the development of clinical weakness in FALS transgenic mice.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Synaptic fatigue is more pronounced in the APP/PS1 transgenic mouse model of Alzheimer's disease.

To search for potential mechanism that might alter synaptic transmission following Abeta increase we have examined the presynaptic component of transmitter release. As parameters of synaptic transmission that might underlie presynaptic mechanisms, we have used paired-pulse facilitation (PPF), post-tetanic potentiation (PTP), and synaptic fatigue (SF) at the connection between the hippocampal Schaffer-collateral pathway and CA1 pyramidal neurons in approximately 5 month old double transgenic mice overexpressing the mutated form of amyloid precursor protein (APPK670N, M671L) and presenilin 1 (PS1M146V). While the presynaptic mechanisms of PPF and PTP were not compromised in the APP/PS1 mice, SF was more pronounced in the double transgenic animals. The percentage of the 40th fEPSP slope over the first during the tetanus was 18 -/+ 3% in APP/PS1 vs. 26 -/+ 2% in WT. Thus, it is likely that presynaptic mechanisms underlying SF but not PPF and PTP, may account for synaptic dysfunction in APP/PS1 mice.

Alzheimer Disease↗
PubMed1995

Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models.

Cancer is a worldwide public health concern. Identifying carcinogens and limiting their exposure is one approach to the problem of reducing risk. Currently, epidemiology and rodent bioassays are the means by which putative human carcinogens are identified. Both methods have intrinsic limitations: they are slow and expensive processes with many uncertainties. The development of methods to modify specific genes in the mammalian genome has provided promising new tools for identifying carcinogens and characterizing risk. Transgenic mice may provide advantages in shortening the time required for bioassays and improving the accuracy of carcinogen identification; transgenic mice might now be included in the testing armamentarium without abandoning the two-year bioassay, the current standard. We show that mutagenic carcinogens can be identified with increased sensitivity and specificity using hemizygous p53 mice in which one allele of the p53 gene has been inactivated. Furthermore, the TG.AC transgenic model, carrying a v-Ha-ras construct, has developed papillomas and malignant tumors in response to a number of mutagenic and nonmutagenic carcinogens and tumor promoters, but not to noncarcinogens. We present a decision-tree approach that permits, at modest extra cost, the testing of more chemicals with improved ability to extrapolate from rodents to humans.

Animals↗
PubMed1989

Transgenic mouse model of familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is a dominantly inherited disorder, characterized by the extracellular deposition of amyloid fibrils composed of variant transthyretin (TTR), and by prominent peripheral nerve involvement. We demonstrate that the main cause of this disease is the presence of a point mutation in the TTR gene. However, neither the time of onset nor the clinical course is predictable. To elucidate the molecular pathogenesis of this disease, we constructed transgenic mice carrying and expressing the human mutant TTR gene. In these mice, amyloid is deposited in the alimentary tract as early as age six months, and becomes more remarkable with aging. These transgenic mice should be useful in elucidating factors which modulate the time of onset and the clinical course of FAP, and in establishing therapy for this intractable disorder.

Amyloidosis↗