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At least 487 records · Page 27Linked to original sources
PubMed2005

Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer.

Overexpression of c-myc and transforming growth factor-alpha (TGF-alpha) has been frequently observed in human hepatocellular carcinoma (HCC),suggesting a pivotal role played by these protooncogenes in liver oncogenesis. In order to investigate the molecular events underlying human hepatic malignant transformation, we have generated c-myc and c-myc/ TGF-alpha transgenic mice that are prone to liver cancer. These transgenic mice develop HCCs with different incidence, kinetics and histopathological features. Indeed, co-expression of c-myc and TGF-alpha transgenes results in a dramatic synergistic effect on liver tumor development when compared with respective single transgenic lines, including a shorter latency period and a more aggressive phenotype. The more malignant histopathological features characteristic of c-myc/ TGF-alpha HCCs are the result of the increased proliferation and reduced apoptosis in this model of liver cancer when compared with single parental lines. Accordingly, c-myc and c-myc/l TGF-alpha transgenic mice display a different molecular pathogenesis of HCC. Importantly, the genetic and molecular mechanisms that are involved in c-myc and c-myc/ TGF-alpha liver cancer development are major oncogenic events in human hepatocarcinogenesis, indicating that these mouse models represent a useful tool to dissect and elucidate the molecular basis of human HCC.

Animals↗
PubMed1998

A transgenic mouse model for mammary carcinogenesis.

Missense mutations in the p53 tumor suppressor occur frequently in human breast cancer and influence both the prognosis and response to chemotherapy. Amino acid 175 (equivalent to murine 172) is the second most common site of missense mutations in p53 in human breast cancer. Over 95% of these mutations are arginine-to-histidine (R-H) substitutions resulting in a gain-of-function, and not merely a dominant-negative phenotype. Transgenic mice expressing a p53 172(R-H) construct targeted to the mammary gland by means of a whey acidic protein (WAP) promoter were characterized as a model system in order to determine the specific effects of this mutation on mammary tumorigenesis. Although transgene expression alone had no apparent effect on normal mammary development, transgenic mice treated with the chemical carcinogen dimethylbenz(a)anthracene developed tumors with much shorter latency than did control littermates and had a greater tumor burden. Tumors arising in transgenic mice did not exhibit either decreased apoptosis or increased cell proliferation relative to tumors arising in nontransgenic littermates, but did display increased genomic instability. Large pleiomorphic nuclei were visible in many tumors from transgenic mice, and DNA flow analysis confirmed the presence of significant aneuploid cell populations. Since these transgenic mice develop very few spontaneous tumors, while accelerating carcinogen-and oncogene-mediated tumorigenesis, this mouse model will, therefore, be useful in the investigation of early events in mammary tumorigenesis. It may also be used as a preclinical model to test newly developed chemotherapeutic strategies.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Hepatitis B virus transgenic mouse model of chronic liver disease.

A model for hepatitis B virus-associated chronic liver disease has been made using cloned hepatitis B virus DNA as a transgene in a severe combined immunodeficient host. These mice consistently support virus gene expression and replication. After adoptive transfer of unprimed, syngeneic splenocytes, these mice cleared virus from liver and serum, and developed chronic liver disease. This model will permit identification of the host and virus contributions to chronic liver disease in the absence of tolerance.

Adoptive Transfer↗
PubMed1996

A transgenic mouse model with an inducible skin blistering disease phenotype.

One of the current limitations of gene transfer protocols involving mammalian genomes is the lack of spatial and temporal control over the desired gene manipulation. Starting from a human keratin gene showing a complex regulation as a template, we identified regulatory sequences that confer inducible gene expression in a subpopulation of keratinocytes in stratified epithelia of adult transgenic mice. We used this cassette to produce transgenic mice with an inducible skin blistering phenotype mimicking a form of epidermolytic hyperkeratosis, a keratin gene disorder. Upon induction by topical application of a phorbol ester, the mutant keratin transgene product accumulates in the differentiating layers of epidermis, leading to keratinocyte lysis after application of mechanical trauma. This mouse model will allow for a better understanding of the complex relationship between keratin mutation, keratinocyte cytoarchitecture, and hypersensitivity to trauma. The development of an inducible expression vector showing an exquisite cellular specificity has important implications for manipulating genes in a spatially and temporally controlled fashion in transgenic mice, and for the design of gene therapy strategies using skin as a tissue source for the controlled delivery of foreign substances.

Animals↗
PubMed2003

Combination of 3' and 5' IgH regulatory elements mimics the B-specific endogenous expression pattern of IgH genes from pro-B cells to mature B cells in a transgenic mouse model.

To ensure the B cell differentiation stage specificity of the intronic Emu element and of the locus control region (LCR) that lies downstream of the IgH chain locus, we generated transgenic mice harboring a V(H) promoter-GFP reporter gene linked to the 3'LCR region and the Emu element. By flow cytometry, GFP(+) lymphocytes were observed amongst pro-B cells (B220(+)CD43(+)CD117(+)) and at all stages of differentiation up to mature B cells (B220(+)IgM(+)IgD(+)). Expression was strictly confined to cells committed to the B lymphocyte lineage as judged by the lack of GFP(+)Thy1,2(+) cells (T lymphocytes) and GFP(+)B220(-)CD117(+)CD43(+) cells (uncommitted lymphohematopoietic progenitors). Therefore, the Emu-GFP-3'LCR transgene is not expressed by hematopoietic stem cells, begins its expression in pro-B cells and is specifically active at all stages of B cell maturation. The combination of 3' and 5' IgH regulatory elements thus appears as a potentially useful cassette in transgenes that require a stringent and early B lineage-specific expression.

Animals↗
PubMed2000

Dual functions of E2F-1 in a transgenic mouse model of liver carcinogenesis.

Deregulation of E2F transcriptional control has been implicated in oncogenic transformation. Consistent with this idea, we recently demonstrated that during hepatocarcinogenesis in c-myc/TGFalpha double transgenic mice, there is increased expression of E2F-1 and E2F-2, as well as induction of putative E2F target genes. Therefore, we generated transgenic mice expressing E2F-1 under the control of the albumin enhancer/promoter to test the hypothesis that E2F family members may contribute to liver tumor development. Overexpression of E2F-1 resulted in mild but persistent increases in cell proliferation and death during postnatal liver growth, and no increases in hepatic regenerative growth in response to partial hepatectomy. Nevertheless, from 2 months postnatally E2F-1 transgenic mice exhibited prominent hepatic histological abnormalities including preneoplastic foci adjacent to portal tracts and pericentral large cell dysplasia. From 6 to 8 months onward, there was an abrupt increase in the number of neoplastic nodules ('adenomas') with 100% incidence by 10 months. Some adenomas showed evidence of malignant transformation, and two of six mice killed at 12 months showed trabecular hepatocellular carcinoma. Endogenous c-myc was up-regulated in the early stages of E2F-1 hepatocarcinogenesis, whereas p53 was overexpressed in the tumors, suggesting that both E2F-1-mediated proliferation and apoptosis are operative but at different stages of hepatocarcinogenesis. In conclusion, E2F-1 overexpression in the liver causes dysplasia and tumors and suggests a cooperation between E2F-1 and c-myc oncogenes during liver oncogenesis.

Albumins↗
PubMedDate not supplied

Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer's disease.

One of the hallmarks of the pathology in Alzheimer's disease is the deposition of amyloid plaques throughout the brain, especially within the hippocampus and amygdala. Transgenic mice that overexpress the Swedish mutation of human amyloid precursor protein (hAPPswe; Tg2576) show age-dependent memory deficits in hippocampus-dependent learning tasks. However, the performance of aged Tg2576 mice in amygdala-dependent learning tasks has not been thoroughly assessed. We trained young (2-4 mo) and old (16-18 mo) Tg2576 and wild-type mice in a T-maze alternation task (hippocampus-dependent) and a Pavlovian fear-conditioning task (amygdala- and hippocampus-dependent). As previously reported, old Tg2576 mice showed impaired acquisition of rewarded alternation; none of these mice reached the criterion of at least five out of six correct responses over three consecutive days. In contrast, old Tg2576 mice showed normal levels of conditional freezing to an auditory conditional stimulus (CS) and acquired a contextual discrimination normally. However, when the salience of the fear-conditioning context was decreased, old (12-14 mo) Tg2576 mice were impaired at acquiring fear to the conditioning context, but not to the tone CS. Histological examination of a subset of the mice verified the existence of amyloid plaques in the cortex, hippocampus, and amygdala of old, but not young, Tg2576 mice. Hence, learning and memory deficits in old Tg2576 mice are limited to hippocampus-dependent tasks, despite widespread amyloid deposition in cortex, hippocampus, and amygdala.

Age Factors↗
PubMed1995

Transgenic mouse models in studies of skeletal disorders.

Studies of mutations in mice and humans are identifying molecular defects in a number of osteochondrodysplasias. Disruption of collagen IX function in mice using 3 transgenic approaches causes a degenerative joint disease resembling osteoarthritis (OA). Mapping of a multiple epiphyseal dysplasia locus to the chromosomal region of COL9A2 suggests that certain heritable forms of OA in humans are also associated with collagen IX mutations. Colocalization of a murine chondrodysplasia, cho, with the Col11a1 locus, as well as mapping of the Stickler syndrome locus to COL11A2, implicate collagen XI genes as other candidates in heritable chondrodysplasias. The murine models permit exploration of pathogenetic mechanisms and testing of novel therapies.

Animals↗
PubMed1995

Expression of a human alpha-1,3/4-fucosyltransferase in the pit cell lineage of FVB/N mouse stomach results in production of Leb-containing glycoconjugates: a potential transgenic mouse model for studying Helicobacter pylori infection.

Helicobacter pylori is a human pathogen associated with the development of gastric and duodenal ulcers and gastric adenocarcinoma. To test the hypothesis that the human Lewis(b) blood group antigen (Le(b)) functions as a receptor for the bacteria's adhesins and mediates its attachment to gastric pit and surface mucous cells, a human alpha-1,3/4-fucosyltransferase was expressed in these cell lineages in FVB/N transgenic mice. The fucosyltransferase directed production of the Leb epitope without any apparent effect on the proliferation and differentiation programs of this lineage. Moreover, clinical isolates of H. pylori bound to these cells in transgenic mice but not in their normal littermates. Binding was blocked by pretreatment of the bacteria with soluble Le(b). This mouse model could be useful for examining the molecular pathogenesis of diseases caused by H. pylori infection. Creating novel pathways for production of specific oligosaccharides in selected cell lineages of transgenic animals represents an approach for examining the role of complex carbohydrates in regulating cellular differentiation and host-microbe interactions.

Animals↗
PubMed2000

A multiple transgenic mouse model with a partially humanized activation pathway for helper T cell responses.

Mice expressing human CD4 and human MHC II molecules provide a valuable model both for the investigation of the immunopathogenetic role of human autoantigens and for the development of therapeutic strategies based on modulating helper T cell activation in vivo. Here we present a novel mouse model expressing HLA-DR17 (a split antigen of HLA-DR3) together with human CD4 in the absence of murine cd4 (CD4/DR3 mice). Human CD4 accurately replaces murine cd4 within T cells. In particular, the preservation of cd8(+) and CD4(+) T cell subsets distinguishes CD4/DR3 mice from other multiple transgenic models in which the alternative T cell subsets are fundamentally disturbed. Moreover, human CD4 is also faithfully expressed on antigen presenting cells such as dendritic cells and monocyte/macrophages, so that the overall transgenic CD4 expression pattern resembles very closely that of humans. HLA-DR3 expression in the thymus correlates very closely to that of mouse MHC II. In contrast, only 70% of mouse MHC II positive cells in spleen, lymph node, and peripheral blood coexpress HLA-DR3. No significant bias was found with regard to particular leucocytes in this respect. The stimulation of helper T cells clearly depends on the interaction between the human transgene products, since mAbs to HLA-DR and/or CD4 completely blocked in vitro recall responses to tetanus toxoid. CD4/DR3 mice represent a partially humanized animal model which will facilitate studies of DR3-associated autoimmune responses and the in vivo determination of the therapeutic potential of mAbs to human CD4.

Animals↗
PubMed1985

A transgenic mouse model of the chronic hepatitis B surface antigen carrier state.

In an attempt to establish a model of the healthy carrier state in hepatitis B virus (HBV) infections, transgenic mice expressing HBV genes were produced. Fertilized one-cell eggs were microinjected with subgenomic fragments of HBV DNA containing the coding regions for the HBV surface antigen (HBsAg) and pre-S and X antigens. Either the normal (HBV) or metallothionein promoters were used to obtain expression of the HBV genes. There was no evidence of viral replication or tissue pathology. The integrated HBV DNA sequences were inherited in a normal Mendelian fashion. Three of 16 transgenic mice expressed HBV-encoded gene products to which they were immunologically tolerant. Expression was not tissue specific and may be influenced by the genomic integration site and cellular factors. Both HBsAg and pre-S antigen were detectable within the cytoplasm of hepatocytes and renal tubular epithelial cells. High serum concentrations of HBsAg were detectable and the secreted product appeared authentic as judged by mean density, morphology, mean particle diameter, polypeptide composition, and antigenicity. The absence of tissue pathology in these immunologically tolerant animals supports the hypothesis that cellular injury under these conditions is not a direct consequence of expression of the pre-S or HBs regions of the HBV genome.

Animals↗
PubMed1997

A transgenic mouse model for human hereditary neuropathy with liability to pressure palsies.

Mutations in the gene encoding peripheral myelin protein 22 (PMP22) account for several inherited peripheral neuropathies in humans. We now show that transgenic mice expressing antisense PMP22 RNA exhibit modestly reduced levels of PMP22 together with a phenotype that is reminiscent of hereditary neuropathy with liability to pressure palsies (HNPP), a human disease caused by a 1.5-Mb deletion of a chromosome 17 region that contains the PMP22 gene. Transgenic antisense homozygotes display a striking movement disorder and a slowing of nerve conduction that worsens with age. Morphological analysis of peripheral nerves demonstrates that a subset of axons have thickened myelin sheaths and tomacula in young adults, with significant myelin degeneration detected in older animals. Together with other recent work, these data suggest that dosage of the PMP22 gene alone underlies the pathophysiology observed in HNPP and related disorders.

Animals↗
PubMed1996

Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis.

A superoxide dismutase 1 (SOD-1)genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degeneration has been described in SOD-1 transgenic mice. Because an excitotoxic mechanism has been implicated in ALS, we undertook studies to provide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-1 transgenic mice. Excitotoxin agonists selective for each of the three major types of inotropic glutamate receptors were applied directly onto the lumbar spinal cord of 21-day old rats following posterior laminectomy. N-methyl-D-aspartate (NMDA) preferentially affected dorsal horn neurons, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely resembled those described in SOD-1 mice. These changes consist of massively swollen dendritic processes in the presence of well-preserved presynaptic axon terminals; cell bodies of motor neurons filled with vacuoles that originate both from endoplasmic reticulum and mitochondria; pleomorphic changes in mitochondria; axons of motor neuron becoming swollen proximally with accumulation of vacuoles, organelles, filaments, and degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS patients. These findings are consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation with non-NMDA glutamate receptors.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Influence of beta1 integrins on epidermal squamous cell carcinoma formation in a transgenic mouse model: alpha3beta1, but not alpha2beta1, suppresses malignant conversion.

Although aberrant integrin expression has been documented in many epithelial tumors, little is known about how integrins influence neoplastic progression. To examine this issue, transgenic mice in which the alpha2beta1 or alpha3beta1 integrin was expressed in the suprabasal epidermal layers via the involucrin promoter were subjected to skin carcinogenesis. Equal numbers of benign squamous papillomas were observed in transgenic and wild-type animals. However, the frequency of conversion of papillomas to malignant squamous cell carcinomas was much lower in alpha3beta1 transgenic than in alpha2beta1 transgenic and wild-type mice. No differences were observed in apoptosis or in the expression of endogenous integrins in transgenic and wild-type papillomas. However, alpha3beta1 transgenic papillomas displayed a diminished proliferative capacity and were more highly differentiated as judged by BrdUrd incorporation and keratin 10 expression, respectively, than alpha2beta1 transgenic and wild-type papillomas. Two proteins that associate with alpha3beta1 and not alpha2beta1 are extracellular matrix metalloproteinase inducer and CD81. Extracellular matrix metalloproteinase inducer expression correlated inversely with the degree of differentiation in normal epidermis and in transgenic and wild-type papillomas. Up-regulation of CD81 was observed in 100% of wild-type and 88% of alpha2beta1 transgenic papillomas but in only 25% of alpha3beta1 transgenic papillomas. CD81 was undetectable in untreated epidermis and strongly expressed in all transgenic and wild-type squamous cell carcinomas. Our results demonstrate that the alpha3beta1 integrin can suppress malignant conversion, and that the mechanism may involve CD81.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Regulation of hepatitis B virus mRNA expression in a hepatitis B surface antigen transgenic mouse model by IFN-gamma-secreting T cells after DNA-based immunization.

The immunotherapeutic effect of DNA-mediated immunization against chronic hepatitis B virus (HBV) infection has been evaluated in transgenic mice expressing the sequences that code for the envelope proteins of HBV in the liver. In this model of HBV chronic carriers, a single i.m. injection of plasmid DNA encoding HBV envelope proteins is sufficient to generate specific immune responses leading to the clearance of the transgene expression product and the control of HBV mRNA. The relative contributions of the T cell subpopulations induced by DNA immunization were examined using adoptive transfer experiments. It was shown that either CD8+ or CD4+ T lymphocytes from immunocompetent DNA-immunized animals were sufficient to control viral gene expression in the livers of the recipient transgenic mice. This effect was mediated by a cytokine-dependent mechanism common to both T cell subpopulations; this mechanism did not require cell lysis, but did involve the production of IFN-gamma by the activated T cells.

Animals↗
PubMed1993

Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis.

The molecular and cellular mechanisms responsible for cytotoxic T lymphocyte (CTL)-induced immunopathology are not well defined. Using a model in which hepatitis B surface antigen (HBsAg)-specific CTL cause an acute necroinflammatory liver disease in HBsAg transgenic mice, we demonstrate that class I-restricted disease pathogenesis is an orderly, multistep process that involves direct as well as indirect consequences of CTL activation. It begins (step 1) almost immediately as a direct antigen-specific CTL-target cell interaction that triggers the HBsAg-positive hepatocyte to undergo programmed cell death (apoptosis). It progresses (step 2) within hours to a focal inflammatory response in which antigen-nonspecific lymphocytes and neutrophils amplify the local cytopathic effect of the CTL. The most destructive pathogenetic function of the CTL, however, is to secrete interferon gamma when they encounter antigen in vivo, thereby activating the intrahepatic macrophage and inducing a delayed-type hypersensitivity response (step 3) that destroys the liver and kills the mouse. We propose that the principles illustrated in this study are generally applicable to other models of class I-restricted, CTL-induced immunopathology, and we suggest that they contribute to the immunopathogenesis of viral hepatitis during hepatitis B virus infection in humans.

Animals↗
PubMed2000

Transgenic mouse models in angiogenesis and cardiovascular disease.

Novel gene technologies have allowed us to manipulate the genetic balance of candidate molecules in mice in a controllable manner. Homologous or site-specific recombination in embryonic stem cells allows us to study the consequences of deficiencies, mutations, and conditional or tissue-specific expression of gene products in transgenic mice. These technological breakthroughs have significantly advanced biomedical research and broadened our understanding of the pathophysiological role of candidate disease genes. In addition, gene transfer allows us to test the possible therapeutic use of gene products for gene therapy. A variety of assays have been miniaturized, allowing analysis of cardiovascular physiology in the mouse. With the advent of genome sequencing programmes, these gene technologies provide means of studying gene function in a conclusive manner. Furthermore, disease models can be generated which can be used as test models for (gene) therapy or for the discovery of novel genes using differential gene profiling techniques. The present review will focus on the molecular basis of how blood vessels form (angiogenesis and arteriogenesis) and how they become diseased. A selected number of molecules that have been studied in the authors' laboratory will be reviewed in more detail.

Animals↗