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At least 235 records · Page 13Linked to original sources
PubMed2003

Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis.

Human cervix cancer is caused by high-risk human papillomaviruses encoding E6 and E7 oncoproteins, each of which alter function of distinct targets regulating the cell cycle, apoptosis, and differentiation. Here we determined the molecular contribution of E6 or E7 to neoplastic progression and malignant growth in a transgenic mouse model of cervical carcinogenesis. E7 increased proliferation and centrosome copy number, and produced progression to multifocal microinvasive cervical cancers. E6 elevated centrosome copy number and eliminated detectable p53 protein, but did not produce neoplasia or cancer. E6 plus E7 additionally elevated centrosome copy number and created large, extensively invasive cancers. Centrosome copy number increases and p53 loss likely contributed to malignant growth; however, dysregulated proliferation and differentiation were required for carcinogenic progression.

Animals↗
PubMed2003

Structural involvement of the glutamatergic presynaptic boutons in a transgenic mouse model expressing early onset amyloid pathology.

While the cholinergic depletion in Alzheimer's disease (AD) has been known for some time, a definitive involvement of other neurotransmitter systems has been somewhat more elusive. Our study demonstrates a clear involvement of both glutamatergic and, to a lesser extent, GABAergic neurons in an early onset transgenic mouse model of AD-like amyloid pathology. Immunohistochemical staining and subsequent quantification has revealed a statistically significant increased density of glutamatergic and GABAergic presynaptic boutons in both the plaque free and plaque adjacent cortical neuropile areas of transgenic mice as compared to non-transgenic controls. Furthermore, amyloid plaque size was shown to have a statistically significant effect on the relative area occupied by dystrophic glutamatergic neurites in the peri-plaque neuropile. These findings support our hypothesis that the amyloid pathology progresses in a time and neurotransmitter specific manner, first in the cholinergic system which appears to be most vulnerable, followed by the glutamatergic presynaptic boutons and finally the somewhat more resilient GABAergic terminals.

Alzheimer Disease↗
PubMed2005

Monitoring disease progression in transgenic mouse models of Alzheimer's disease with proton magnetic resonance spectroscopy.

Currently no definitive biomarker of Alzheimer's disease (AD) is available, and this impedes both clinical diagnosis in humans and drug discovery in transgenic animal models. Proton magnetic resonance spectroscopy ((1)H MRS) provides a noninvasive way to investigate in vivo neurochemical abnormalities. Each observable metabolite can potentially provide information about unique in vivo pathological processes at the molecular or cellular level. In this study, the age-dependent 1H MRS profile of transgenic AD mice was compared to that of wild-type mice. Twenty-seven APP-PS1 mice (which coexpress mutated human presenilin 1 and amyloid-beta precursor protein) and 30 wild-type mice age 66-904 days were examined, some repeatedly. A reduction in the levels of N-acetylaspartate and glutamate, compared with total creatine levels, was found in APP-PS1 mice with advancing age. The most striking finding was a dramatic increase in the concentration of myo-inositol with age in APP-PS1 mice, which was not observed in wild-type mice. The age-dependent neurochemical changes observed in APP-PS1 mice agree with results obtained from in vivo human MRS studies. Among the different transgenic mouse models of AD that have been studied with 1H MRS, APP-PS1 mice seem to best match the neurochemical profile exhibited in human AD. 1H MRS could serve as a sensitive in vivo surrogate indicator of therapeutic efficacy in trials of agents designed to reduce neurotoxicity due to microglial activation. Because of its noninvasive and repeatable nature, MRS in transgenic models of AD could substantially accelerate drug discovery for this disease.

Alzheimer Disease↗
PubMed2004

Transgenic mouse model of early-onset DYT1 dystonia.

Early-onset dystonia is an autosomal dominant movement disorder associated with deletion of a glutamic acid residue in torsinA. We generated four independent lines of transgenic mice by overexpressing human DeltaE-torsinA using a neuron specific enolase promoter. The transgenic mice developed abnormal involuntary movements with dystonic-appearing, self-clasping of limbs, as early as 3 weeks after birth. Animals also showed hyperkinesia and rapid bi-directional circling. Approximately 40% of transgenic mice from each line demonstrated these severe behavioral abnormalities. Neurochemical analyses revealed decreases in striatal dopamine in affected transgenic mice, although levels were increased in those that had no behavioral changes. Immunohistochemistry demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin, torsinA and lamin, a marker of the nuclear envelope. Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to what has been described in DYT1 patients. This transgenic mouse model demonstrates behavioral and pathologic features similar to patients with early-onset dystonia and may help to better understand the pathophysiology of this disorder and to develop more effective therapies.

Amino Acid Sequence↗
PubMed2006

E2F3a stimulates proliferation, p53-independent apoptosis and carcinogenesis in a transgenic mouse model.

Mutation or inactivation of the retinoblastoma (Rb) tumor suppressor occurs in most human tumors and results in the deregulation of several members of the E2F family of transcription factors. Among the E2F family, E2F3 has been implicated as a key regulator of cell proliferation and E2F3 gene amplification and overexpression is detected in some human tumors. To study the role of E2F3 in tumor development, we established a transgenic mouse model expressing E2F3a in a number of epithelial tissues via a keratin 5 (K5) promoter. Transgenic expression of E2F3a leads to hyperproliferation, hyperplasia and increased levels of p53-independent apoptosis in transgenic epidermis. Consistent with data from human cancers, the E2F3a transgene is found to have a weak oncogenic activity on its own and to significantly enhance the response to a skin carcinogenesis protocol. The phenotype of K5 E2F3a transgenic mice is distinct from similar transgenic mice expressing E2F1 or E2F4. In particular, E2F3a has a unique apoptotic activity and lacks the tumor suppressive property of E2F1 in this model system.

Animals↗
PubMed2000

Absence of p53: no effect in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Familial amyotrophic lateral sclerosis (ALS) has been linked in some families to dominantly inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (Cu-Zn SOD1). Transgenic mice expressing a mutant human Cu-Zn SOD1 (G93A) develop a dominantly inherited adult-onset paralytic disorder that replicates many of the clinical and pathological features of familial ALS. Increased p53 immunoreactivity has been reported in the motor cortex and spinal ventral horns of postmortem tissue from ALS patients. The nuclear phosphoprotein p53 is an important regulator of cellular proliferation, and increasing evidence supports the role of p53 in regulating cellular apoptosis. To assess the role of p53-mediated apoptosis in amyotrophic lateral sclerosis, mice deficient in both p53 alleles (p53-/-) were crossed with transgenic mice expressing the G93A mutant (G93A+), creating novel transgenic knockout mice. The animals (p53 +/+G93A+, p53+/-G93A+, p53-/-G93A+) were examined at regular intervals for cage activity, upper and lower extremity strength, and mortality. At 120 days from birth mice from each genotype were sacrificed, and L2-L3 anterior horn motor neurons were counted. There was no significant difference in time to onset of behavioral decline, mortality, or motor neuron degeneration between the different genotypes. Despite evidence that p53 plays an important role after acute neuronal injury, the current study suggests that p53 is not significantly involved in cell death in the G93A+ transgenic mouse model of familial ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Interleukin-6 gene ablation in a transgenic mouse model of malignant skin melanoma.

Interleukin (IL)-6 is a pleiotropic cytokine that has been shown to inhibit the growth of early stage and to promote the proliferation of advanced stage melanoma cells in vitro. In patients with metastasizing melanomas, highly increased IL-6 blood levels correlate with a poor response to chemotherapy and a worse overall prognosis, suggesting that IL-6 promotes melanoma progression in vivo. Here, we analyzed the role of IL-6 in melanoma development and progression in a transgenic mouse model. We bred IL-6-deficient mice with MT-ret transgenic animals predisposed for melanomas. While MT-ret transgenic animals develop severe melanosis of the skin and subcutis and subsequent melanomas at an incidence of 80% during their first year of life, MT-ret mice devoid of IL-6 developed preneoplastic melanosis and consecutive melanomas significantly less frequently (47%; P < 0.05). Moreover, the tumors were significantly smaller in the groups of MT-ret mice lacking one (P < 0.05) or both (P < 0.01) copies of the IL-6 gene. Immunoblot analysis revealed that ret transgene expression was not reduced in the skin of mice lacking IL-6, indicating that the observed decrease of melanoma incidence and of tumor sizes was not because of a down-regulation of transgene expression. Taken together, these results indicate that IL-6 enhances both the development of melanoma precursor lesions and the subsequent growth of the resulting tumors in the MT-ret model of melanoma development.

Animals↗
PubMed1996

Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model.

Overexpression of the c-myc oncogene is associated with a variety of both human and experimental tumors, and cooperation of other oncogenes and growth factors with the myc family are critical in the evolution of the malignant phenotype. The interaction of hepatocyte growth factor (HGF) with c-myc during hepatocarcinogenesis in a transgenic mouse model has been analyzed. While sustained overexpression of c-myc in the liver leads to cancer, coexpression of HGF and c-myc in the liver delayed the appearance of preneoplastic lesions and prevented malignant conversion. Furthermore, tumor promotion by phenobarbital was completely inhibited in the c-myc/HGF double transgenic mice, whereas phenobarbital was an effective tumor promoter in the c-myc single transgenic mice. The results indicate that HGF may function as a tumor suppressor during early stages of liver carcinogenesis, and suggest the possibility of therapeutic application for this cytokine.

Animals↗
PubMed2000

Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.

Recent data suggest that cholesterol metabolism is linked to susceptibility to Alzheimer's disease (AD). However, no direct evidence has been reported linking cholesterol metabolism and the pathogenesis of AD. To test the hypothesis that amyloid beta-peptide (Abeta) deposition can be modulated by diet-induced hypercholesterolemia, we used a transgenic-mouse model for AD amyloidosis and examined the effects of a high-fat/high-cholesterol diet on central nervous system (CNS) Abeta accumulation. Our data showed that diet-induced hypercholesterolemia resulted in significantly increased levels of formic acid-extractable Abeta peptides in the CNS. Furthermore, the levels of total Abeta were strongly correlated with the levels of both plasma and CNS total cholesterol. Biochemical analysis revealed that, compared with control, the hypercholesterolemic mice had significantly decreased levels of sAPPalpha and increased levels of C-terminal fragments (beta-CTFs), suggesting alterations in amyloid precursor protein processing in response to hypercholesterolemia. Neuropathological analysis indicated that the hypercholesterolemic diet significantly increased beta-amyloid load by increasing both deposit number and size. These data demonstrate that high dietary cholesterol increases Abeta accumulation and accelerates the AD-related pathology observed in this animal model. Thus, we propose that diet can be used to modulate the risk of developing AD.

Alzheimer Disease↗
PubMed2003

Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease.

Epidemiological studies of Alzheimer patients from a wide variety of ethnic and socioeconomic backgrounds have identified education and occupation as environmental factors that can affect the risk of developing disease. A model of environmental manipulation in rodents uses enriched housing to provide cognitive and social stimulation. Previous studies have established elevations in synaptic number and function in rodents housed under enriched conditions. Recent experiments in hippocampal cultures have demonstrated that synaptic activity can influence the processing of amyloid precursor protein (APP). Here we examined whether changes in synaptic activity brought about by enriched housing might also influence the deposition of amyloid plaques in vivo using a transgenic mouse model of Alzheimer disease (AD). Mice co-expressing mutant APP and presenilin 1 (PS1) were housed in either enriched or standard cages from 2 months of age and then killed for pathological evaluation several months later. We find that, as compared to littermates housed in standard cages, the enriched APP/PS1 transgenic mice develop a higher amyloid burden with commensurate increases in aggregated and total A beta. These results suggest that A beta deposition can be exacerbated by the neuronal changes associated with enrichment, and demonstrate a substantial, albeit paradoxical, environmental influence on the progression of pathology in a mouse model of AD.

Alzheimer Disease↗
PubMed2004

The stress or heat shock (HS) response: insights from transgenic mouse models.

Since its discovery, stress or heat shock (HS) response has been widely studied as a paradigm for gene regulation. From control of gene expression to function and involvement in pathological processes, different aspects of the stress response have received extended attention and investigation by various approaches, using small analyzing molecules, cells and organisms. This chapter is focused on animal models, such as transgenic mice that allow integrated analysis of intact organisms in physiological and pathological conditions. Genetically modified mice, developed to generate gain- and loss-of-function, are described. The challenges of using the transgenic mouse model are also discussed.

Animals↗
PubMed2006

Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease.

Normal age-related testosterone depletion in men is a recently identified risk factor for Alzheimer's disease (AD), but how androgen loss affects the development of AD is unclear. To investigate the relationship between androgen depletion and AD, we compared how androgen status affects the progression of neuropathology in the triple transgenic mouse model of AD (3xTg-AD). Adult male 3xTg-AD mice were sham gonadectomized (GDX) or GDX to deplete endogenous androgens and then exposed for 4 months to either the androgen dihydrotestosterone (DHT) or to placebo. In comparison to gonadally intact 3xTg-AD mice, GDX mice exhibited robust increases in the accumulation of beta-amyloid (Abeta), the protein implicated as the primary causal factor in AD pathogenesis, in both hippocampus and amygdala. In parallel to elevated levels of Abeta, GDX mice exhibited significantly impaired spontaneous alternation behavior, indicating deficits in hippocampal function. Importantly, DHT treatment of GDX 3xTg-AD mice attenuated both Abeta accumulation and behavioral deficits. These data demonstrate that androgen depletion accelerates the development of AD-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, our finding that DHT protects against acceleration of AD-like neuropathology predicts that androgen-based hormone therapy may be a useful strategy for the prevention and treatment of AD in aging men.

Aging↗
PubMed2006

TGF-betal transgenic mouse model of thoracic irradiation: modulation of MMP-2 and MMP-9 in the lung tissue.

To investigate the effects of TGF-beta1 on the two gelatinases (MMP-2 and MMP-9), and their roles in lung remodeling after irradiation-induced lung injury. Expressions of TGF-beta1 were measured with western blot, and expressions of MMP-2 and MMP-9 were analyzed with zymography in a -TGF-beta1 transgenic mouse model after thoracic irradiation with 12 Gy. We found expressions of TGF-beta1 in the lung from the transgenic mice were three folds as compared to those from control mice. With densitometrical analysis, we found a significant decrease in MMP-9 activity in lung homogenates from the transgenic mice as compared with those from non-transgenic control mice 8 weeks after sham-irradiation (relative MMP-9 activity: C: 1.000 0.1091; TG: 0.4772 +/- 0.470 (n = 8, P < 0.05). But MMP-2 was constitutively expressed in the lung homogenates from the transgenic mice as compared to those from control mice 8 weeks after sham-irradiation (relative MMP-2 activity 8 weeks after sham-irradiation: C: 1.000 +/- 0.1556, TG: 1.0075 +/- 0.1472). Eight weeks after thoracic irradiation with 12 Gy, we observed a significant increase of MMP-2 and MMP-9 activity in lung homogenates from both transgenic and normal mice. In TGF-beta1 transgenic mice relative MMP-9 activity was increased to 1.5321 +/- 0.2217 folds 8 weeks after thoracic irradiation with 12 Gy as compared to those after sham-irradiation (1.000 +/- 0.2153), and relative MMP-2 activity was increased to 1.7142 +/- 0.4231 folds. Our results show that TGF-beta1 itself down-regulates activity of MMP-9, thereby decreases ECM degradation in lungs of TGF-beta1 transgenic mice. Also we find that ionizing irradiation upregulates both MMP-2 and MMP-9 activity. Over-expressions of MMP-9 and MMP-2 after lung irradiation are involved in the inflammatory response associated with radiation-induced lung injury, and maybe further in radiation-induced lung fibrosis.

Animals↗
PubMed2005

Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism.

OBJECTIVES: The Q192R polymorphism of paraoxonase (PON1) has been shown to affect hydrolysis of organophosphorus compounds. The Q192 and R192 alloforms exhibit equivalent catalytic efficiencies of hydrolysis for diazoxon, the oxon form of the pesticide (DZ). However, the R192 alloform has a higher catalytic efficiency of hydrolysis than does the Q192 alloform for chlorpyrifos oxon (CPO), the oxon form of the pesticide chlorpyrifos (CPS). The current study examined the relevance of these observations for in-vivo exposures to chlorpyrifos and chlorpyrifos oxon. METHODS: Using a transgenic mouse model we examined the relevance of the Q192R polymorphism for exposure to CPS and CPO in vivo. Transgenic mice were generated that expressed either human PON1Q192 or PON1R192 at equivalent levels, in the absence of endogenous mouse PON1. Dose-response and time course experiments were performed on adult mice exposed dermally to CPS or CPO. Morbidity and acetylcholinesterase (AChE) activity in the brain and diaphragm were determined in the first 24 h following exposure. RESULTS: Mice expressing PON1Q192 were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1R192. The time course of inhibition following exposure to 1.2 mg/kg CPO revealed maximum inhibition of brain AChE at 6-12 h, with PON1R192, PON1Q192, and PON1 mice exhibiting 40, 70 and 85% inhibition, respectively, relative to control mice. The effect of PON1 removal on the dose-response curve for CPS exposure was remarkably consistent with a PBPK/PD model of CPS exposure. CONCLUSION: These results indicate that individuals expressing only the PON1Q192 allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1Q192.

Acetylcholinesterase↗
PubMed1998

Selective deposition of amyloid-beta protein in the entorhinal-dentate projection of a transgenic mouse model of Alzheimer's disease.

Early and selective deposition of amyloid beta protein(Abeta) is thought to be a pathological feature central to Alzheimer's disease (AD). It has been a great challenge to identify the mechanism(s) responsible for the selectivity of Abeta deposition and the deposition into a temporal sequence of the pathogenesis in this disorder. We now report that the transgenic mouse (PDAPP), which overexpresses the human amyloid precursor protein containing the familial AD mutation (APP717V-F), develops brain region-specific Abeta deposits along with some pathologies associated with AD. By using monoclonal antibodies that recognize multiple sites on the human Abeta peptide, we show that Abeta deposits are localized primarily to the entorhinal cortex and hippocampal/dentate gyrus regions. Abeta deposition exhibited consistent laminar distribution throughout the hippocampal formation that was confined mostly to a dense terminal field in the outer portion of the stratum moleculare of the dentate gyrus and the stratum lacunosum of the hippocampus proper of 13-month-old heterozygous PDAPP mice. Abeta deposits were also observed in the supragranular zone of the dentate gyrus. Similarly, laminar distribution of Abeta deposits were evident in the entorhinal cortex, most notably in the molecular layer and in laminar layer II-III. The defined laminar pattern of the Abeta deposition, which resembles that of AD, suggests that intrinsic factors in the perforant path, the major projection from the entorhinal cortex to the hippocampal formation, and their respective local paths contribute, at least in part, to the extracellular Abeta deposition in the transgenic mouse model of AD.

Alzheimer Disease↗
PubMed2005

Cultured cell and transgenic mouse models for tau pathology linked to beta-amyloid.

The two histopathological signatures of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles, prompting speculation that a causal relationship exists between the respective building blocks of these abnormal brain structures: the beta-amyloid peptides (Abeta) and the neuron-enriched microtubule-associated protein called tau. Transgenic mouse models have provided in vivo evidence for such connections, and cultured cell models have allowed tightly controlled, systematic manipulation of conditions that influence links between Abeta and tau. The emerging evidence supports the view that amyloid pathology lies upstream of tau pathology in a pathway whose details remain largely mysterious. In this communication, we review and discuss published work about the Abeta-tau connection. In addition, we present some of our own previously unpublished data on the effects of exogenous Abeta on primary brain cultures that contain both neurons and glial cells. We report here that continuous exposure to 5 microM non-fibrillar Abeta40 or Abeta42 kills primary brain cells by apoptosis within 2-3 weeks, Abeta42 is more toxic and selective for neurons than Abeta40, and Abeta42, but not Abeta40, induces a transient increase in neurons that are positive for the AD-like PHF1 epitope. These findings demonstrate the greater potency of Abeta42 than Abeta40 at inducing tau pathology and programmed cell death, and corroborate and extend reports that tau-containing cells are more sensitive to Abeta peptides than cells that lack or express low levels of tau.

Amyloid beta-Peptides↗
PubMed2002

Evaluation of a transgenic mouse model for anti-human CEA radioimmunotherapeutics.

UNLABELLED: In this study, a human carcinoembryonic antigen (CEA) transgenic (CEA.Tg) mouse model was evaluated for the preclinical assessment of agents directed against CEA. METHODS: Cell-type and organ-specific expression of CEA was studied in CEA.Tg mice derived from a colony that carries the complete human CEA gene together with flanking regulatory sequences and also in wild-type controls. Biodistribution studies were performed on wild-type and CEA.Tg mice by intravenous injection of 125I-labeled anti-CEA (PR1A3) or isotype control (IC) murine monoclonal antibodies (mAbs). Studies were also performed on tumor-bearing CEA.Tg and nude mice. RESULTS: As with humans, the CEA.Tg mice had low serum levels of CEA (mean, 8.8 +/- 5.52 ng/mL), and cell-surface CEA expression was primarily localized in the gastrointestinal tract. Both mAbs showed similar biodistribution patterns in the wild-type mice, whereas in the CEA.Tg mice, PR1A3 specifically localized to the CEA-expressing tissues. In the gastrointestinal tract, the percentage injected dose for PR1A3 was significantly higher than that for IC mAb at all the time points sampled. In CEA.Tg mice bearing a murine tumor transfected with human CEA, PR1A3 targeted tissues with constitutive CEA expression and was retained at the tumor site at high levels, whereas in nude mice, PR1A3 localized only to the site of the transplanted tumor. CONCLUSION: These results demonstrate the targeting potential of the anti-CEA antibody, PR1A3, and emphasize the value of using a transgenic model in preclinical studies.

Animals↗
PubMed2004

A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype.

Human neuroendocrine cancers (NECs) arise in various endoderm-derived epithelia, have diverse morphologic features, exhibit a wide range of growth phenotypes, and generally have obscure cellular origins and ill-defined molecular mediators of initiation and progression. We describe a transgenic mouse model of metastatic gastric cancer initiated by expressing simian virus 40 large tumor antigen (SV40 TAg), under control of regulatory elements from the mouse Atp4b gene, in the progenitors of acid-producing parietal cells. Parietal cells normally do not express endocrine or neural features, and Atp4b-Cre bitransgenic mice with a Cre reporter confirmed that the Atp4b regulatory elements are not active in gastric enteroendocrine cells. GeneChip analyses were performed on laser capture microdissected SV40 TAg-expressing cells in preinvasive foci and invasive tumors. Genes that distinguish invasive from preinvasive cells were then hierarchically clustered with DNA microarray datasets obtained from human lung and gastric cancers. The results, combined with immunohistochemical and electron microscopy studies of Apt4b-SV40 TAg stomachs, revealed that progression to invasion was associated with transdifferentiation of parietal cell progenitors to a neuroendocrine phenotype, and that invasive cells shared molecular features with NECs arising in the human pulmonary epithelium, including transcription factors that normally regulate differentiation of various endocrine lineages and maintain neural progenitors in an undifferentiated state. The 399 mouse genes identified as regulated during acquisition of an invasive phenotype and concomitant neuroendocrine transdifferentiation, plus their human orthologs associated with lung NECs, provide a foundation for molecular classification of NECs arising in other tissues and for genetic tests of the molecular mechanisms underlying NEC pathogenesis.

Animals↗