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Results for “Transgenic mouse model”

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At least 433 records · Page 24Linked to original sources
PubMed1999

Dose-response resistance to HIV-1/MuLV pseudotype virus ex vivo in a hairpin ribozyme transgenic mouse model.

We have investigated the efficacy of a hairpin ribozyme targeting the 5' leader sequence of HIV-1 RNA in a transgenic model system. Primary spleen cells derived from transgenic or control mice were infected with HIV-1/MuLV pseudotype virus. A significantly reduced susceptibility to infection in ribozyme-expressing transgenic spleen cells (P = 0.01) was shown. Variation of transgene-expression levels between littermates revealed a dose response between ribozyme expression and viral resistance, with an estimated cut off value below 0.2 copies of hairpin ribozyme per cell. These findings open up possibilities for studies on ribozyme efficacy and anti-HIV-1 gene therapy.

Animals↗
PubMed2004

Up-regulation and altered distribution of lysyl oxidase in the central nervous system of mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis.

Mutations of the copper-zinc superoxide dismutase (SOD1) gene can result in the development of amyotrophic lateral sclerosis (ALS). The exact cellular mechanisms causing ALS are not known, but oxidative stress is thought to play a prominent role. Lysyl oxidase (LOX) is one of the genes that are known to be up-regulated in ALS patients. In this study, we examined LOX localization in wild type rat and mouse brain sections using immunohistochemistry coupled with laser-scanning confocal microscope. The results showed that LOX, an extracellular matrix protein, was expressed in the choroid plexus, blood vessel walls, brain matrix, and neurons of normal rat and mice. In neurons, LOX was localized within the cytoplasm. LOX immunoreactivity increased in neurons of the spinal cord, brain stem and cortex, and the Purkinje cells of the cerebellum in transgenic G93A SOD1 (mSOD1) mouse model of ALS. In situ hybridization indicated that LOX gene expression was enhanced in the neurons of the spinal cord, brain stem, cortex, caudoputamen and cerebellum in mSOD1 mice compared with wild type controls. LOX enzyme activity was increased in mSOD1 mice. An increase in the amount of LOX mRNA, protein and enzyme activity was coincidental with late stage ALS, indicating that LOX may be associated with the progression of the neurodegenerative process in the mSOD1 model of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Age-dependent impairment of somatosensory response in the amyloid precursor protein 23 transgenic mouse model of Alzheimer's disease.

Quantitative functional magnetic resonance imaging was applied to characterize brain function in amyloid precursor protein 23 (APP23) transgenic mice, which reproduce the neuropathological alterations associated with Alzheimer's disease. Electrical stimulation of the paw led to cerebral blood volume increases in the contralateral somatosensory cortex. In APP23 mice this hemodynamic response decreased with increasing age of the animal and with increasing stimulus amplitude as compared with wild-type animals. The age-dependent dysfunction in APP23 mice may be attributed in part to a compromised cerebrovascular reactivity. Quantitative functional brain mapping that uses standardized sensory inputs should allow for assessment of disease progression and therapy response (e.g., passive immunization against beta-amyloid) in patients also.

Age Factors↗
PubMed1993

A transgenic mouse model for studying the lineage relationships and differentiation program of type II pneumocytes at various stages of lung development.

A pedigree of transgenic mice has been characterized that contains a H2-Kb/LacZ fusion gene that exhibits integration site-dependent expression from the earliest stages of lung development through adulthood. Histochemical and immunocytochemical studies indicate that the LacZ reporter appears throughout the pulmonary endoderm by embryonic day 11 (E11). A proximal-to-distal wave of extinction of transgene expression occurs during E13-14 that parallels the wave of cytodifferentiation of the pulmonary endoderm. By E16, the LacZ reporter is restricted to the distal portion of epithelial tubules and by birth to scattered cells located in alveoli. Crude epithelial cell suspensions were prepared from lungs harvested from E16 and 14 day postnatal transgenic mice, labeled with the fluorescent LacZ substrate fluorescein di-(beta-galactopyranoside), and the LacZ expressing population isolated by fluorescence-activated cell sorting. Electron microscopic, immunocytochemical and histochemical studies of this purified cell population establish that type II pneumocytes are the only cell lineage that support H2-Kb/LacZ expression in the mature postnatal lung. Fluorescence-activated cell sorting of E16 lung suspensions yielded a homogeneous population of cells that produced surfactant protein A, that could be maintained in cell culture, and that are likely precursors of adult type II pneumocytes. Together these studies indicate that (i) expression of the transgene in this pedigree of mice provides a marker for describing early differentiation of the pulmonary epithelium; (ii) the transgene may be useful as an enhancer trap to isolate cis-acting sequences that regulate gene transcription within this lineage; (iii) the LacZ reporter expression can be used to purify specific embryonic pulmonary epithelial cell populations; and (iv) primary cultures of these embryonic populations represent a potentially useful model system for analyzing the cellular components and signaling pathways necessary to support and complete passage through the type II pneumocyte differentiation program.

Aging↗
PubMed1997

A transgenic mouse model of hemoglobin S Antilles disease.

Hemoglobin (Hb) S Antilles is a naturally occurring form of sickling human Hb but causes a more severe phenotype than Hb S. Two homozygous viable Hb S Antilles transgene insertions from Tg58Ru and Tg98Ru mice were bred into MHOAH mice that express high oxygen affinity (P50 approximately 24.5 mm Hg) rather than normal (P50 approximately 40 mm Hg) mouse Hbs. The rationale was that the high oxygen affinity MHOAH Hb, the lower oxygen affinity of Hb S Antilles than Hb S (P50 approximately 40 v 26.5 mm Hg), and the lower solubility of deoxygenated Hb S Antilles than Hb S (approximately 11 v 18 g/dL) would favor deoxygenation and polymerization of human Hb S Antilles in MHOAH mouse red blood cells (RBCs). The Tg58 x Tg98 mice produced have a high and balanced expression (approximately 50% each) of h alpha and h beta(S Antilles) globins, 25% to 35% of their RBCs are misshapen in vivo, and in vitro deoxygenation of their blood induces 30% to 50% of the RBCs to form classical looking, elongated sickle cells with pointed ends. Tg58 x Tg98 mice exhibit reticulocytosis, an elevated white blood cell count and lung and kidney pathology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic intervention of sickle cell disease.

Anemia, Sickle Cell↗
PubMed1999

Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA.

Dentatorubral and pallidoluysian atrophy (DRPLA) is a member of a family of progressive neurodegenerative diseases caused by polyglutamine repeat expansion. Transgenic mice expressing full-length human atrophin-1 with 65 consecutive glutamines exhibit ataxia, tremors, abnormal movements, seizures, and premature death. These mice accumulate atrophin-1 immunoreactivity and inclusion bodies in the nuclei of multiple populations of neurons. Subcellular fractionation revealed 120 kDa nuclear fragments of mutant atrophin-1, whose abundance increased with age and phenotypic severity. Brains of DRPLA patients contained apparently identical 120 kDa nuclear fragments. By contrast, mice overexpressing atrophin-1 with 26 glutamines were phenotypically normal and did not accumulate the 120 kDa fragments. We conclude that the evolution of neuropathology in DRPLA involves proteolytic processing of mutant atrophin-1 and nuclear accumulation of truncated fragments.

Adolescent↗
PubMed1996

Differential induction of carcinogen metabolizing enzymes in a transgenic mouse model of fulminant hepatitis.

The objective of this work is to examine the possible modulation of carcinogen metabolism (activation by cytochrome P450s and detoxification by conjugation via glutathione S-transferases [GST]) in relation to hepatitis B virus (HBV)-associated liver injury. In HBV transgenic mouse lineage 107.5, the hepatitis B surface antigen (HBsAg) is expressed at noncytopathic concentrations but after injection of an HBsAg-specific, major histocompatibility complex (MHC) class I restricted cytotoxic T-lymphocyte (CTL) clone, the mice develop a severe acute necroinflammatory liver disease that reaches maximum severity within 3 days and gradually subsides during the next 2 to 3 weeks. In this model, using immunohistochemical analysis, we observed an increase of P450s (CYP1A and 2A5), both involved in aflatoxin B1, metabolism, but minor changes or no changes for others (2B, 2C, 2E, 3A). There was a fivefold decrease in the total liver P450 microsomal content 3 days' post-CTL injection with the result that the relative proportion of CYP2A5 and 1A compared with other P450s is increased. Individual microsomal P450 enzyme contents estimated by Western blotting; Northern blot analysis of liver CYP messenger RNA (mRNA) levels as well as in vitro metabolism of specific substrates for different P450 isoenzymes were consistent with the immunohistochemical data. Immunohistochemical staining with antibodies to cytosolic pi class GST was increased 1 and 3 days postinjection followed by a progressive decrease at later time points (the same phenomenon was observed to a lesser extent for GST alpha). The activity of hepatic cytosols toward substrates specific for different subclasses of GST (mu, pi, alpha) showed that while GST mu was not changed in the CTL-injected HBV transgenic mice, GST pi and, to a lesser extent, alpha were increased as compared with controls. These results suggest that liver cell injury induced by a process of acute fulminant-like hepatitis can lead to the induction of some carcinogen metabolizing enzymes notably, Cyp 1A, 2A5 and GST pi in the mouse.

Animals↗
PubMed1993

In vivo mutagenesis induced by CC-1065 and adozelesin DNA alkylation in a transgenic mouse model.

Although considerable work has focused on characterizing the bonding chemistry and sequence selective alkylation of DNA by cyclopropylpyrroloindole compounds, little is known about the molecular consequence of their N-3-adenine adducts in whole animal systems. We have utilized a transgenic mouse system, harboring a lambda phage shuttle vector, to assess the mutagenic potential of the antitumor compounds CC-1065 and adozelesin and, for the first time, to track the in vivo fate of their unique DNA modifications at the nucleotide level. Mice were inoculated with a single therapeutic dose of these agents and sacrificed at either 18 h, 3 days, or 15 days for extraction and analysis of liver DNA. Mutant frequencies obtained from drug treated and control animals were determined by in vitro packaging of the phage vector from genomic DNA followed by a colorimetric plaque assay to screen for phage in which the accompanying lacI repressor gene had mutated. Although undetectable at 18 h posttreatment, by 72 h a 3-fold increase in mutant frequency was observed in drug treated animals such that sequence analysis of drug induced mutations could be performed and a direct comparison made between in vitro and in vivo DNA alkylation. Base substitution involving guanine or cytosine accounted for 64% of the 41 mutations sequenced from drug treated animals. Only 7 of the mutations occurred at a cyclopropylpyrroloindole alkylation site while 23 occurred 1 to 4 nucleotides from a potentially alkylated adenine.

Alkylation↗
PubMed2002

A transgenic mouse model for non-immune hydrops fetalis induced by the NS1 gene of human parvovirus B19.

Human parvovirus B19 (B19) infection during pregnancy is associated with the adverse foetal outcome known as non-immune hydrops fetalis (NIHF). Although B19 is known to infect erythroid-lineage cells in vivo as well as in vitro, the mechanism leading to the occurrence of NIHF is not clear. To investigate the possible involvement of the B19 non-structural protein NS1 in NIHF, three independent lines of transgenic mice were generated that expressed NS1 under the control of the Cre-loxP system and the GATA1 promoter. Two of the three lines expressed NS1 in erythroid-lineage cells. Most of the transgenic mice died at the embryonic stage, some of which developed hydropic changes caused by severe anaemia at embryonic day 15.5 (E15.5). Histological examination of embryos at E15.5 showed significantly fewer erythropoietic islands in the liver parenchyma, whereas their hearts showed no abnormal signs, such as cardiomegaly and apoptotic cells. The NS1-transgenic mouse lines established here provide an animal model for human NIHF and suggest that NS1 plays a crucial role in the adverse outcome associated with intrauterine B19 infection in humans.

Animals↗
PubMed2004

Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition.

The role of microglia in the removal of amyloid deposits after systemically administered anti-Abeta antibodies remains unclear. In the current study, we injected Tg2576 APP transgenic mice weekly with an anti-Abeta antibody for 1, 2, or 3 months such that all mice were 22 months at the end of the study. In mice immunized for 3 months, we found an improvement in alternation performance in the Y maze. Histologically, we were able to detect mouse IgG bound to congophilic amyloid deposits in those mice treated with the anti-Abeta antibody but not in those treated with a control antibody. We found that Fcgamma receptor expression on microglia was increased after 1 month of treatment, whereas CD45 was increased after 2 months of treatment. Associated with these microglial changes was a reduction in both diffuse and compact amyloid deposits after 2 months of treatment. Interestingly, the microglia markers were reduced to control levels after 3 months of treatment, whereas amyloid levels remained reduced. Serum Abeta levels and anti-Abeta antibody levels were elevated to similar levels at all three survival times in mice given anti-Abeta injections rather than control antibody injections. These data show that the antibody is able to enter the brain and bind to the amyloid deposits, likely opsonizing the Abeta and resulting in Fcgamma receptor-mediated phagocytosis. Together with our earlier work, our data argue that all proposed mechanisms of anti-Abeta antibody-mediated amyloid removal can be simultaneously active.

Amyloid↗
PubMed2004

Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis.

OBJECTIVES: To study the expression of cysteine proteinases, particularly cathepsin K, and their extracellular inhibitor cystatin C in articular cartilage of transgenic Del1 mice which harbour a short deletion mutation in a type II collagen transgene and are predisposed to early onset osteoarthritis. METHODS: Northern analysis was used to measure mRNA levels of cathepsins B, H, K, L, and S, and cystatin C in total RNA extracted from knee joints of Del1 mice, using their non-transgenic litter mates as controls. Immunohistochemistry and morphometry was used to study the distribution of cathepsin K and cystatin C in the knee joints. RESULTS: Up regulation of cathepsin K mRNA expression was seen in the knee joints of transgenic Del1 mice at the onset of cartilage degeneration. Cathepsin K was found near sites of matrix destruction in articular chondrocytes, particularly in clusters of proliferating cells, and in calcified cartilaginous matrix. In intact articular cartilage of control animals, cathepsin K was only seen in a small number of chondrocytes. Upon aging, control animals also developed osteoarthritis, which was accompanied by increased cathepsin K expression. Cystatin C was mostly localised in and around chondrocytes located in calcified cartilage, with no obvious association with the onset of cartilage degeneration. CONCLUSION: The temporospatial distribution of cathepsin K in osteoarthritic cartilage suggests a role for this enzyme in the pathogenesis of osteoarthritis. Because cathepsin K can digest cartilage matrix components it may contribute to the development of osteoarthritic lesions. These data may provide new clues for the development of treatments aimed at preventing cartilage degeneration.

Animals↗
PubMed1996

Functional analysis of human tissue kallikrein in transgenic mouse models.

Clinical studies show that an inverse correlation exists between blood pressure and urinary kallikrein levels. It has been postulated that the tissue kallikrein-kinin system contributes to the maintenance of normal blood pressure. To test this hypothesis, we have established transgenic mice that overexpress human tissue kallikrein under the promoter control of the mouse metallothionein gene and a liver-targeted albumin gene. These animals secrete human tissue kallikrein in plasma at levels 10- to 40-fold higher than that found in normal human serum, and they are chronically hypotensive. This hypotensive effect can be reversed by the injection of aprotinin, a potent tissue kallikrein inhibitor, or Hoe 140, a specific bradykinin receptor antagonist. Transgenic mice overexpressing human tissue kallikrein show a sustained reduction in blood pressure throughout their life spans, indicating the lack of sufficient compensatory mechanisms to reverse the hypotensive effect of kallikrein. Somatic gene delivery of rat kallikrein-binding protein by muscle injection increases the blood pressure of the hypotensive transgenic mice to levels comparable with those in normotensive control mice. These results indicate that a direct link exists between kallikrein gene expression and alterations in blood pressure. In addition, we have developed normotensive transgenic mice that harbor the human tissue kallikrein gene containing 801 bp of its native promoter. The tissue distribution pattern of human kallikrein in these transgenic mice is similar to that in human tissues, with the highest level in the pancreas and much lower levels in the kidney and salivary gland. These transgenic mice provide new animal models for investigating the tissue-specific regulation of tissue kallikrein and its role in altering blood pressure.

Animals↗
PubMed2001

A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease.

Clinical, epidemiological, and laboratory studies suggest that cholesterol may play a role in the pathogenesis of Alzheimer's disease (AD). Transgenic mice exhibiting an Alzheimer's beta-amyloid phenotype were treated with the cholesterol-lowering drug BM15.766 and tested for modulation of beta-amyloid levels. BM15.766 treatment reduced plasma cholesterol, brain Abeta peptides, and beta-amyloid load by greater than twofold. A strong, positive correlation between the amount of plasma cholesterol and Abeta was observed. Furthermore, drug treatment reduced the amyloidogenic processing of the amyloid precursor protein, suggesting alterations in processing in response to cholesterol modulation. This study demonstrates that hypocholesterolemia is associated with reduced Abeta accumulation suggesting that lowering cholesterol by pharmacological means may be an effective approach for reducing the risk of developing AD.

Alzheimer Disease↗
PubMed1998

Oncostatin M stimulates excessive extracellular matrix accumulation in a transgenic mouse model of connective tissue disease.

Oncostatin M (OM), a member of the IL-6 gene family, stimulates a variety of functions implicated in wound repair. Transgenic mice that express this cytokine in islet beta-cells develop a connective tissue disorder that typifies excessive healing with severe fibrosis and lymphocytic infiltration. To compare this phenotype with the normal progression of connective tissue disease, we measured the expression patterns of genes encoding proinflammatory cytokines, fibrogenic cytokines, and ECM components by in situ hybridization. To test whether the OM effect was caused by its ability to regulate IL-6, we crossed the OM transgene into IL-6-deficient mice. Our data suggest that the fibrosis in these animals is not a secondary consequence of inflammation, or IL-6 expression, but is a direct effect by OM on extracellular matrix production. In a separate experiment, we observed that OM could regulate vasoactive intestinal peptide gene expression in the neurons that innervate the transgenic pancreas. This nerve healing response, in combination with its fibrogenic activity, suggests that OM functions downstream of inflammation in the wound repair cascade. These transgenic mice represent a useful model in which the fibroproliferative phase of connective tissue disease is uncoupled from inflammation.

Animals↗
PubMed1998

Enhanced morphine-induced behavioural effects and dopamine release in the nucleus accumbens in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: influence of long-term treatment with the antidepressant moclobemide.

In vivo microdialysis experiments were conducted in transgenic mice with impaired glucocorticoid receptor function resulting from expression of antisense directed against glucocorticoid receptor messenger RNA. Basal corticosterone and serotonin levels in the nucleus accumbens of untreated transgenic mice were enhanced compared to control mice (B6C3F1). Following a systemic morphine injection (15 mg/kg) mesolimbic dopamine and serotonin release was markedly increased in transgenic mice compared to control mice and in parallel enhanced behavioural stimulation was observed in these animals. After pretreatment with the antidepressant moclobemide over a time period of eight weeks (15 mg/kg/day) elevated basal levels of both corticosterone and serotonin were normalized in transgenic mice. Furthermore, morphine-induced dopamine and serotonin release as well as behavioral stimulation were suppressed in transgenic mice and similar to that in control mice. The results indicate that impaired glucocorticoid receptor function influences the basal release of serotonin in the nucleus accumbens. This alteration has no effect on basal but on morphine-stimulated release of dopamine in the mesolimbic system. An enhanced sensitivity to the effects of morphine is apparently related to elevated brain corticosterone and serotonin levels and can be normalized by long-term antidepressant treatment.

Animals↗
PubMed2006

Insights from a transgenic mouse model on the role of SLC26A2 in health and disease.

Mutations in the SLC26A2 cause a family of recessive chondrodysplasias that includes in order of decreasing severity achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia and recessive multiple epiphyseal dysplasia. The gene encodes for a widely distributed sulfate/chloride antiporter of the cell membrane whose function is crucial for the uptake of inorganic sulfate that is needed for proteoglycan sulfation. To investigate the mechanisms leading to skeletal dysplasia, we generated a transgenic mouse with a mutation in Slc26a2 causing a partial loss of function of the sulfate transporter. Homozygous mutant mice were characterized by skeletal dysplasia with chondrocytes of irregular size, delay in the formation of the secondary ossification centre and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts and fibroblasts, but proteoglycan undersulfation was detected only in cartilage. The similarity with human diastrophic dysplasia makes this mouse a model to explore pathogenetic and therapeutic aspects of SLC26A2-related disorders.

Animals↗