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Results for “Transgenic mouse model”

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At least 631 records · Page 35Linked to original sources
PubMed1997

Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Mutations in the gene encoding copper/zinc superoxide dismutase enzyme produce an animal model of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis. Overexpression of the proto-oncogene bcl-2 delayed onset of motor neuron disease and prolonged survival in transgenic mice expressing the FALS-linked mutation in which glycine is substituted by alanine at position 93. It did not, however, alter the duration of the disease. Overexpression of bcl-2 also attenuated the magnitude of spinal cord motor neuron degeneration in the FALS-transgenic mice.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Chronic changes in peripheral growth hormone levels do not affect ghrelin stomach mRNA expression and serum ghrelin levels in three transgenic mouse models.

Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor. Ghrelin is involved in feeding behaviour and is a potent stimulator of GH release. Chronically increased GH concentrations are known to negatively regulate the pituitary GHS receptor. This study tested whether chronic changes in peripheral GH levels/action affect ghrelin mRNA expression and circulating concentrations of ghrelin. Stomach ghrelin mRNA expression and serum concentrations of ghrelin were measured in three groups of transgenic mice and the respective control animals: group 1, GH-receptor gene disrupted mice (GHR/KO); group 2, mice expressing bovine GH (bGH); and group 3, mice expressing GH-antagonist (GHA). Ghrelin mRNA expression in the stomach, pituitary and hypothalamus of young adult male rats were measured using reverse-transcription-polymerase chain reaction. Ghrelin mRNA expression levels were approximately 3000-fold higher in rat stomach than in rat pituitary. Ghrelin mRNA expression in rat hypothalamus was below the detection limits of our assay. Stomach ghrelin mRNA expression, as well as serum concentrations of ghrelin, did not change significantly in any of the three mouse groups compared to the respective control group. These data support previous observations that the stomach is the main source of circulating ghrelin, and also indicate that stomach ghrelin mRNA expression and serum concentrations of ghrelin are not affected by chronic changes in peripheral GH/insulin-like growth factor-I levels/action.

Animals↗
PubMed1996

A new transgenic mouse model for the study of cell cycle control in megakaryocytes.

During the development of the megakaryocytic lineage, the megakaryoblasts give rise to megakaryocytes which undergo repeated S phases in the absence of cytokinesis (endomitosis). The cellular oncogene myc plays a central role in the proliferation and differentiation of several cell types. In a previous study, we generated transgenic mice carrying c-myc fused to the estrogen receptor under the control of the platelet factor four (PF4) megakaryocyte-specific promoter. The bone marrow of female transgenic mice, but not of male mice, displayed increased megakaryopoiesis. Here we report that beta-estradiol-induced activation of c-myc in cultured bone marrow cells derived from male or female transgenic mice resulted in prolonged survival of the cells in vitro. Addition of a cocktail of hemopoietic growth factors to beta-estradiol-treated cells, including interleukin 6 (IL-6), IL-3 and stem cell factor further improved the survival time in culture and increased the percentage of large mature cells, but did not result in immortalization. The majority of these PF4-expressing cells, however, did not reach the differentiation stage at which acetylcholinesterase is expressed and did not appear as large megakaryocytes. We conclude that cultured megakaryocytes overexpressing myc are induced to proliferate, but have a limited potential to fully differentiate. Under these conditions, cyclin D3 was downregulated while the level of cyclin A was slightly upregulated.

Acetylcholinesterase↗
PubMed2004

Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease.

Evidence suggests N-methyl-D-aspartate receptor (NMDAR) activation is involved in the degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). We tested the hypothesis that enhanced NMDAR-mediated excitotoxicity is mediated by the mitochondrial-associated apoptotic pathway in cultured MSNs from YAC transgenic mice expressing full-length huntingtin (htt) with a polyglutamine (polyQ) expansion of 46 or 72 (YAC46 or YAC72). NMDAR-mediated Ca(2+) transients and mitochondrial membrane depolarization were significantly increased in YAC compared to wild-type mice MSNs. Inhibitors of the mitochondrial permeability transition (mPT), cyclosporin A and bongkrekic acid, and coenzyme Q10 (an anti-oxidant involved in bioenergetic metabolism) dramatically diminished NMDA-induced cell death and eliminated genotypic differences. In YAC46 MSNs, NMDA stimulated significantly higher activation of caspase-3 and caspase-9 but not caspase-8, and NMDA-induced caspase-3 and -9 activation was markedly attenuated by cyclosporin A. Agents that improve mitochondrial function or inhibit the permeability transition may eliminate increased caspase activation and cell death associated with enhanced NMDAR activity in HD.

Animals↗
PubMed1991

Transgenic mouse model for central nervous system demyelination.

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.

Animals↗
PubMed2006

Analysis of intrahepatic lymphocyte subsets in a transgenic mouse model of immune-mediated hepatocarcinogenesis.

Long-term, persistent liver cell injury increases the risk for hepatocellular carcinoma (HCC) development in chronic viral hepatitis. In support of this notion, we have developed a unique animal model of chronic immune-mediated liver disease that induces hepatocellular carcinogenesis using HBV transgenic mice; however, the intrahepatic inflammatory response was not precisely evaluated. The current study demonstrated that hepatitis B surface antigen (HBsAg)-specific cytotoxic T lymphocytes (CTLs) were detected at a frequency of 0.05% of CD8+ T lymphocytes in the liver, and that monocytes/macrophages were remarkably increased as the disease developed. These results suggest that a minimal number of intrahepatic virus-specific CTLs and the recruited monocytes/macrophages may contribute to the process of chronic liver inflammation.

Animals↗
PubMed1994

Elevation of neuronal MAO-B activity in a transgenic mouse model does not increase sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

To examine whether expressing high levels of monoamine oxidase (MAO-B) activity abberently in neurons results in increased sensitivity of dopaminergic neurons to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 8-week-old transgenic mice expressing high neuronal levels of MAO-B were compared with age-matched nontransgenic littermates following i.p. injections of 30 mg/kg body weight of the protoxin. Levels of striatal dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), as well as tyrosine hydroxylase (TH)-immunopositive cell numbers in the substantia nigra (SN) were compared 1 week later between transgenics and controls. No difference was found in any of these parameters, indicating that high neuronal MAO-B levels does not cause increased sensitivity to MPTP, and therefore neither conversion of MPTP to its active form, 1-methyl-4-phenyl pyridium (MPP+) by MAO-B nor MPP+ uptake by the dopaminergic transporter are likely to be the rate-limiting step in the toxicity of this compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

T cell receptor-transgenic mouse models for studying cellular immune responses to Salmonella in vivo.

Cellular immune responses are crucial both for protective immunity against salmonellosis, and for the immunogenicity of oral vaccines based on avirulent live Salmonella as antigen carriers. The crucial early steps of T cell induction are difficult to investigate in conventional animals, but recently developed T cell receptor (TCR)-transgenic models allow visualization of antigen-specific T cells in vivo while they become induced. In this review, the results obtained with four different TCR-transgenic Salmonella infection models are described, and advantages and potential limits of each of the different models are compared.

Animals↗
PubMed2003

No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the beta-cleaved C-terminal APP fragment.

Previous studies in the literature have resulted in conflicting reports on the potential neurotoxicity of the beta-cleaved Alzheimer's disease C-terminal fragment (beta-CTF) of beta-amyloid precursor protein in vivo. To readdress this question by rigorous quantitative methods, we analyzed transgenic mice expressing human beta-CTF with the I45F mutation (SPA4CT) under control of the prion protein promoter by stereological techniques. The transgene was expressed in hippocampus and cortex in large pyramidal neurons and in dentate gyrus granule cells. Proteolytic processing of beta-CTF released Abeta. However, most of it remained uncleaved. Neurodegeneration was evaluated by investigating the numbers of hippocampal pyramidal and granule neurons, as well as the number of synaptophysin-immunopositive presynaptic boutons in the hippocampus of 15-month-old SPA4CT mice with design-based stereological techniques. The analyses showed that a fourfold higher expression of the transgene compared to murine APP levels had no effect on the numbers of both neurons and synaptophysin-immunopositive presynaptic boutons. These data implicate that expression of beta-CTF per se is not neurotoxic, and that other mechanisms are responsible for the neurotoxic events in Alzheimer's disease brain.

Alzheimer Disease↗
PubMed1997

Biology of TGF-beta in knockout and transgenic mouse models.

This paper reviews the basic biology and biochemistry of the TGF-beta isoforms including their unique serine-threonine receptors and signaling intermediates. Dysregulation of TGF-beta expression and/or receptor/signaling function have been implicated in a wide variety of pathologies. We will discuss mechanisms underlying some of these disease processes as gained from study of transgenic mice in which expression of TGF-beta 1 has either been lost by targeted deletion of its gene, is overexpressed in a tissue-specific manner, or blocked by its latency associated peptide.

Albumins↗
PubMed1997

Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brain stem. About 10% of all ALS cases are familial (FALS), inherited in an autosomal dominant manner. One fifth of FALS patients carry mutations in the Cu/Zn superoxide dismutase (SOD1) gene, and several lines of transgenic mice have been engineered to express mutant forms of the SOD1 gene that are linked to FALS. Significantly, many of these transgenic lines of mice develop a motor neuron disease (MND) that resembles human FALS. Oxidative stress induced by human SOD1 mutations is believed to play an important role in the pathogenesis of FALS and the FALS-like MND seen in the mutant SOD1 transgenic mice. For example, two lines of these mice showed prominent degeneration of mitochondria and endoplasmic reticulum in spinal cord neurons. Furthermore, recent studies have shown that neurofilament (NF)-rich spheroids. Lewy body-like NF inclusions, altered ubiquitin immunoreactivity, and Golgi fragmentation occur in the spinal cord motoneurons of these mutant SOD1 transgenic mice. Because these lesions recapitulate hallmark abnormalities of human ALS, mutant SOD1 transgenic mice provide a useful model for studies designed to elucidate the pathogenesis of ALS. Furthermore, transgenic mice that overexpress NF proteins also develop a clinical and pathologic phenotype similar to human MND, and polymorphisms in an NF gene have been linked to patients with ALS. Collectively, these observations implicate NF protein abnormalities in the pathogenesis of this disorder. Accordingly, this review summarizes recent insights into mechanisms of motor neuron degeneration in ALS that have emerged from studies of these new animal models of this neurodegenerative disease.

Amyotrophic Lateral Sclerosis↗
PubMed1999

A transgenic mouse model to analyze CD8(+) effector T cell differentiation in vivo.

Antigen-specific effector T cells are prerequisite to immune protection, but because of the lack of effector cell-specific markers, their generation and differentiation has been difficult to study. We report that effector cells are highly enriched in a T cell subset that can be specifically identified in transgenic (T-GFP) mice expressing green fluorescent protein (GFP) under control of the murine CD4 promoter and proximal enhancer. Consistent with previous studies of these transcriptional control elements, GFP was strongly and specifically expressed in nearly all resting and short-term activated CD4(+) and CD8(+) T cells. However, when T-GFP mice were challenged with vaccinia virus, allogeneic tumor cells, or staphylococcal enterotoxin A, the cytotoxic and IFN-gamma-producing T cells lost GFP expression. Upon T cell receptor (TCR) ligation by alphaCD3, sorted GFP(+) cells fluxed calcium and proliferated vigorously. In contrast, GFP(-) effector cells showed a diminished calcium flux and did not proliferate. Instead, they underwent apoptosis unless supplied with exogenous IL-2. By reverse transcription-PCR analysis, the GFP(-) cells up-regulated the pro-apoptotic molecule, Fas-L, and down-regulated gene expression of the proximal TCR signaling molecule, CD3zeta, and c-jun, a component of the AP-1 transcription factor. Thus, differential regulation of TCR signaling may explain the divergent responses of naïve and effector T cells to antigen stimulation.

Animals↗
PubMed2006

Tissue-specific sensitivity to AID expression in transgenic mouse models.

Activation-induced cytidine deaminase (AID), an enzyme with homology to members of the APOBEC family, is involved in somatic hypermutation (SHM) of immunoglobulin (Ig) genes, either by direct deamination of DNA or by an indirect action through its putative RNA editing activity. AID is able to mutate both Ig-like reporter constructs and selected non-Ig genes in normal B cells and in other cells when ectopically overexpressed in mammalian cells and transgenic mice. However, in spite of the fact that in these transgenic animals AID activity was driven by an ubiquitous promoter, only T lymphomas and lung adenomas occurred. In the present work, we constructed three sets of transgenic mice in which AID was under the control of lck, HTLV-I and MMTV promoters, respectively. The lck/AID mice developed thymic lymphomas with variable but high efficiency, while no tumor was detected in HTLV-I/AID mice after two years of monitoring. Four MMTV/AID founder mice died with an atypical clinical picture, although no mammary tumor was found. These findings suggest that additional factors, present in thymocytes but not in other tissues or in lymphoid cells at different stages of differentiation, are needed for AID to fully manifest its tumorigenic potential in mouse. Alternatively, the display of full AID mutagenic and transforming activity could be related to the existence of physiologic DSBs which occur in both thymocytes and switching B cells.

Animals↗