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At least 703 records · Page 39Linked to original sources
PubMed2004

Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome.

BACKGROUND: We identified a gene (PRKAG2) that encodes the gamma-2 regulatory subunit of AMP-activated protein kinase (AMPK) with a mutation (Arg302Gln) responsible for familial Wolff-Parkinson-White (WPW) syndrome. The human phenotype consists of ventricular preexcitation, conduction abnormalities, and cardiac hypertrophy. METHODS AND RESULTS: To elucidate the molecular basis for the phenotype, transgenic mice were generated by cardiac-restricted expression of the wild-type (TG(WT)) and mutant(TG(R302Q)) PRKAG2 gene with the cardiac-specific promoter alpha-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG(R302Q) mice to have ventricular preexcitation (PR interval 10+/-2 versus 33+/-5 ms in TG(WT), P<0.05) and a prolonged QRS (20+/-5 versus 10+/-1 ms in TG(WT), P<0.05). A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia. Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009+/-0.003 versus 0.025+/-0.001 nmol x min(-1) x g(-1) in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site. Excessive cardiac glycogen was observed. Hypertrophy was confirmed by increases in heart weight (296 versus 140 mg in TG(WT)) and ventricular wall thickness. CONCLUSIONS: We have developed a genetic animal model of WPW that expresses a mutation responsible for a familial form of WPW syndrome with a phenotype identical to that of the human, including induction of supraventricular arrhythmia. The defect is due to loss of function of AMPK. Elucidation of the molecular basis should provide insight into development of the cardiac conduction system and accessory pathways.

AMP-Activated Protein Kinases↗
PubMed2003

Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation.

A beta peptides are the major protein constituents of Alzheimer's disease (AD) senile plaques and also form some deposits in the cerebrovasculature leading to cerebral amyloid angiopathy and hemorrhagic stroke. Functional vascular abnormalities are one of the earlier clinical manifestations in both sporadic and familial forms of AD. Most of the cardiovascular risk factors (for instance, diabetes, hypertension, high cholesterol levels, atherosclerosis and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of A beta on endothelin-1 induced vasoconstriction in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized A beta enhances endothelin-1 induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoactive effect of A beta in these large human cerebral arteries is inhibited by NS-398, a selective cyclooxygenase-2 inhibitor and by SB202190, a specific p38 Mitogen Activated Protein Kinase inhibitor suggesting the involvement of a pro-inflammatory pathway. Using a scanner laser Doppler imager, we observed that cerebral blood flow is decreased in the double transgenic APPsw Alzheimer mouse (PS1/APPsw) compared to PS1 littermates and can be improved by chronic treatment with either NS-398 or SB202190. Altogether, our data suggest a link between inflammation and the compromised cerebral hemodynamics in AD.

Aged↗
PubMed2003

Expression of the low affinity neurotrophin receptor p75 in spinal motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a lethal neurodegenerative disorder involving motoneuron loss in the cortex, brainstem and spinal cord, resulting in progressive paralysis. Aberrant neurotrophin signalling via the low affinity neurotrophin receptor p75 has been suggested to be involved in the motoneuron death by the activation of apoptotic pathways. In order to investigate the involvement of neurotrophin receptor p75 in the amyotrophic lateral sclerosis related motoneuron degeneration process, we have studied the expression of this receptor in the spinal cord of transgenic mice carrying a mutated human Cu, Zn superoxide dismutase gene. Mutations in the superoxide dismutase gene are one of the genetic causes for familiar amyotrophic lateras sclerosis and human superoxide dismutase-1 transgenic mice develop symptoms and pathology similar to those in human amyotrophic lateras sclerosis. Our study shows that in these mice, spinal motoneurons, which normally do not contain the neurotrophin receptor p75 receptor, express this receptor during the progress of the disease. Expression of the neurotrophin receptor p75 receptor coincides with the expression of activating transcription factor 3, a member of the activating transcription factor/cyclic AMP family of stress transcription factors. Only a minority of these spinal motoneurons actually showed co-expression of neurotrophin receptor p75 with caspase-3 activity, suggesting that expression of the neurotrophin receptor p75 receptor is not directly related to the execution phase of the apoptosis process.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Development of a transgenic mouse model susceptible to human coronavirus 229E.

Human coronavirus (HCoV) 229E is a group 1 coronavirus and is specific to humans. So far, no animal model is available to study the pathogenesis of infection by HCoV-229E. We show here that the expression of aminopeptidase N (APN, also termed CD13), the receptor for HCoV-229E, is required but not sufficient to confer susceptibility in vivo. HCoV-229E infection was facilitated by crossing APN transgenic mice into signal transducers and activators of transcription (Stat) 1 null mice and by adaptation of HCoV-229E to grow in primary APN transgenic, Stat1 null fibroblasts. Double transgenic mice allow the study of human coronavirus group 1 infections in an animal model, in particular, viral tropism, replication, recombination, and spread in an immunocompromised situation. Furthermore, these mice provide an important tool for the evaluation of biosafety and efficacy of coronavirus-based vectors.

Animals↗
PubMed2002

Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer.

BACKGROUND: It is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2. METHODS: Experimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4+ T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches. RESULTS: In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival. CONCLUSIONS: The results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity.

Adoptive Transfer↗
PubMed2006

In vivo characterization of endothelial cell activation in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD is characterized by an excessive cerebral amyloid deposition leading to degeneration of neurons and eventually to dementia. It has been shown by epidemiological studies that cardiovascular drugs with an anti-angiogenic effect can influence the outcome of AD patients. Therefore, it has been speculated that in AD angiogenesis in the brain vasculature may play an important role. Here we report that in the brain of APP23 mice--a transgenic model of AD--after deposition of amyloid in blood vessels endothelial cell activation occurs in an age-dependent manner. Amyloid deposition is followed by the expression of beta3-integrin, a specific marker molecule of activated endothelium. The beta3-integrin expression is restricted to amyloid-positive vessels. Moreover, homogenates of the brains of APP23 mice induced the formation of new vessels in an in vivo angiogenesis assay. Vessel formation could be blocked by the VEGF antagonist SU 4312 as well as by statins, suggesting that these drugs may interfere with endothelial cell activation in AD. In conclusion our results indicate that amyloid deposition in the vasculature leads to endothelial cell apoptosis and endothelial cell activation, which can be modulated by anti-angiogenic drugs.

Aging↗
PubMed1997

Evaluation of sunscreens with various sun protection factors in a new transgenic mouse model of cutaneous photoaging that measures elastin promoter activation.

BACKGROUND: Long-term sun exposure can cause major alterations in the papillary dermis, resulting in the deposition of massive amounts of abnormal elastic material, termed solar elastosis. Previous work has demonstrated that this type of photodamage is accompanied by an increase in elastin and fibrillin messenger RNAs and elastin promoter activity. OBJECTIVE: Our purpose was to develop a rapid and sensitive in vivo method for evaluating compounds offering protection against cutaneous photodamage. METHODS: Using a line of transgenic mice that expresses the human elastin promoter linked to a chloramphenicol acetyltransferase reporter gene, we applied sunscreens with various sun protection factors to 5-day-old mice followed by 30 minimal erythema doses of solar simulating radiation for three consecutive days. RESULTS: Solar simulating radiation alone resulted in a fivefold increase in elastin promoter activity. Sun protection factors of 2, 4, 8, and 15 yielded a reduction in promoter activity by 2.8%, 42.5%, 58.1%, and 70.3%, respectively. CONCLUSION: These results confirm the use of this system as a rapid and sensitive in vivo model for evaluating compounds that protect against photodamage.

Animals↗
PubMed2001

The roles of ATF3 in glucose homeostasis. A transgenic mouse model with liver dysfunction and defects in endocrine pancreas.

Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element-binding protein family of transcription factors. It is a transcriptional repressor, and the expression of its corresponding gene is induced by stress signals in a variety of tissues, including the liver. In this report, we demonstrate that ATF3 is induced in the pancreas by partial pancreatectomy, streptozotocin treatment, and ischemia coupled with reperfusion. Furthermore, ATF3 is induced in cultured islet cells by oxidative stress. Interestingly, transgenic mice expressing ATF3 in the liver and pancreas under the control of the transthyretin promoter have defects in glucose homeostasis and perinatal lethality. We present evidence that expression of ATF3 in the liver represses the expression of genes encoding gluconeogenic enzymes. Furthermore, expression of ATF3 in the pancreas leads to abnormal endocrine pancreas and reduced numbers of hormone-producing cells. Analyses of embryos indicated that the ATF3 transgene is expressed in the ductal epithelium in the developing pancreas, and the transgenic pancreas has fewer mitotic cells than the non-transgenic counterpart, providing a potential explanation for the reduction of endocrine cells. Because ATF3 is a stress-inducible gene, these mice may represent a model to investigate the molecular mechanisms for some stress-associated diseases.

Activating Transcription Factor 3↗
PubMed2004

Transgenic mouse models support HCR as an effector gene in the PSORS1 locus.

Genetic susceptibility for psoriasis is regulated to the greatest extent by the PSORS1 locus. Three psoriasis-associated susceptibility alleles have been identified within it, namely, HLACw6, HCR*WWCC and CDSN*5, but strong linkage disequilibrium between them has made it difficult to distinguish their individual genetic effects, and animal models to study their effects are not known. To study the function of HCR, we engineered transgenic mice with either a non-risk allele of HCR or the HCR*WWCC risk allele under the control of the cytokeratin-14 promoter. These choices were motivated by the apparently dominant effect of PSORS1 on psoriasis susceptibility and the physiological expression of HCR in basal keratinocytes. Transgenic mice appeared phenotypically normal and histologically their skin was indistinguishable from wild-type mice. Expression studies using Affymetrix arrays suggested that the HCR risk allele has specific functional consequences relevant to the pathogenesis of psoriasis. Comparison of gene expression changes between non-risk and risk allele mice revealed similarities to previous observations in human psoriatic skin, including upregulation of cytokeratins 6, 16 and 17 in risk allele mice. We also observed changes in the expression of genes associated with terminal differentiation and formation of the cornified cell envelope. Our results support the concept that HCR may constitute an essential gene in the PSORS1 locus. These observations are also compatible with a model that a susceptibility gene for psoriasis induces changes that are contributory but not sufficient by itself to produce the clinical phenotype.

Animals↗
PubMed2004

JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors.

The human polyomavirus, JC virus, has recently been associated with several human CNS tumors, including medulloblastomas and a broad range of glial-origin tumors. This ubiquitous virus is the causative agent of the rare demyelinating disease, progressive multifocal leukoencephalopathy in immunocompromised individuals. Expression of the viral protein, T-antigen, which possesses the ability to transform cells of neural origin, has been detected in human CNS tumors. In an effort to further understand the transforming potential of JCV T-antigen, transgenic mice expressing JCV T-antigen under the control of the Mad-4 promoter were generated. As described previously, approximately 50% of the animals developed pituitary tumors by 1 year of age. However, a small subset of the animals developed solid masses arising from the soft tissues surrounding the salivary gland, the sciatic nerve, and along the extremities that histologically resemble malignant peripheral nerve sheath tumors, rare neoplasms that occur in individuals with neurofibromatosis type 1 (NF1). JCV T-antigen was detected in tumor tissue by immunohistochemistry and immunoprecipitation/Western blotting, but not in normal tissues and was colocalized with NF2, the putative tumor suppressor protein associated with neurofibromatosis type 2, in the nucleus of some cells. In addition, T-antigen was co-precipitated with NF2, but not with NF1 protein, although NF1 was detectable in tumor tissue. Furthermore, precipitated immunocomplexes contained T-antigen, NF2, and p53, suggesting that these three proteins may form a ternary complex. The importance of these findings on mechanisms of T-antigen-mediated tumorigenesis and the pathogenesis of neurofibromatosis are discussed. Oncogene (2004) 23, 5459-5467. doi:10.1038/sj.onc.1207728 Published online 10 May 2004

Animals↗
PubMed2005

Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The disease is caused by highly stereotyped mutations in NOTCH3, which is restrictively expressed in vascular smooth muscle cells (VSMCs). The mechanisms of compromised cerebral hemodynamics in CADASIL remain to be elucidated. We tested the hypothesis that mutant NOTCH3 impairs the vasomotor function of cerebral vessels. METHODS: Vasomotor function was examined in vivo in transgenic mice expressing a mutant NOTCH3 in VSMCs (TgNotch3R90C). Mice develop an age-dependent arteriopathy similar to that seen in CADASIL, without brain parenchyma lesions. Using laser-Doppler flowmetry, we assessed in awake TgNotch3R90C mice and wild-type littermates the cerebrovascular reactivity to 2 potent vasodilator stimuli (acetazolamide and hypercapnia) and cerebral blood flow (CBF) autoregulation during stepwise blood pressure elevations and reductions. Mice were studied at 18 months of age, when the CADASIL features are apparent, and at 10 months of age, before their appearance. RESULTS: Eighteen-month-old TgNotch3R90C mice showed reduced responses to hypercapnia and acetazolamide, higher cerebrovascular resistance during hypertension, and their lower limit of CBF autoregulation was shifted to higher blood pressures. Cerebrovascular responses were similarly impaired in 10-month-old TgNotch3R90C mice. CONCLUSIONS: Cerebrovascular reactivity is compromised early in TgNotch3R90C mice. The data show an impaired autoregulation and are suggestive of a decreased relaxation or increased resistance of cerebral vessels. Our findings indicate that vascular dysfunction is an early pathogenic event that may promote the subsequent development of brain ischemia in CADASIL.

Acetazolamide↗
PubMed2002

IL-6 transgenic mouse model for extraosseous plasmacytoma.

Plasma cell neoplasms in humans comprise plasma cell myeloma, otherwise known as multiple myeloma, Ig deposition and heavy chain diseases, and plasmacytoma (PCT). A subset of PCT, designated extramedullary PCT, is distinguished from multiple myeloma and solitary PCT of bone by its distribution among various tissue sites but not the bone marrow. Extramedullary (extraosseus) PCT are rare spontaneous neoplasms of mice but are readily induced in a susceptible strain, BALB/c, by treatment with pristane. The tumors develop in peritoneal granulomas and are characterized by Myc-activating T(12;15) chromosomal translocations and, most frequently, by secretion of IgA. A uniting feature of human and mouse plasma cell neoplasms is the critical role played by IL-6, a B cell growth, differentiation, and survival factor. To directly test the contribution of IL-6 to PCT development, we generated BALB/c mice carrying a widely expressed IL-6 transgene. All mice exhibited lymphoproliferation and plasmacytosis. By 18 months of age, over half developed readily transplantable PCT in lymph nodes, Peyer's patches, and sometimes spleen. These neoplasms also had T(12;15) translocations, but remarkably, none expressed IgA. Unexpectedly, approximately 30% of the mice developed follicular and diffuse large cell B cell lymphomas that often coexisted with PCT. These findings provide a unique model of extramedullary PCT for studies on pathogenesis and treatment and suggest a previously unappreciated role for IL-6 in the genesis of germinal center-derived lymphomas.

Animals↗
PubMed2000

A transgenic mouse model for tumour immunotherapy: induction of an anti-idiotype response to human MUC1.

MUC1 is a membrane bound, polymorphic epithelial mucin expressed at the luminal surface of glandular epithelium. It is highly expressed in an underglycosylated form on carcinomas and metastatic lesions and is, therefore, a potential target for immunotherapy of cancer. The monoclonal antibody HMFG1 binds the linear core protein sequence, PDTR, contained within the immunodominant domain of the tandem repeat of MUC1. The efficacy of murine and humanized HMFG1 (Ab1) used as an anti-idiotypic vaccine was examined in mice transgenic for human MUC1 (MUC1.Tg) challenged with murine epithelial tumour cells transfected with human MUC1. Humoral idiotypic cascade through Ab2 and Ab3 antibodies was observed in MUC1.Tg mice following multiple antibody inoculations in the presence of adjuvant. Impaired tumour growth at day 35 and highest Ab3 levels were found in mice that had received mHMFG1 with RAS adjuvant. However, comparison of Ab3 levels in individual mice with tumour size in all treatment groups did not show a correlation between smaller tumours and increased levels of anti-idiotype antibody. This suggests that the anti-tumour effects of anti-idiotype vaccination are not solely related to the induction of idiotypic antibody cascades and probably involve other mechanisms.

Adjuvants, Immunologic↗
PubMed2005

A transgenic mouse model of heart failure using inducible Galpha q.

Receptors coupled to Galpha q play a key role in the development of heart failure. Studies using genetically modified mice suggest that Galpha q mediates a hypertrophic response in cardiac myocytes. Galpha q signaling in these models is modified during early growth and development, whereas most heart failure in humans occurs after cardiac damage sustained during adulthood. To determine the phenotype of animals that express increased Galpha q signaling only as adults, we generated transgenic mice that express a silent Galpha q protein (Galpha qQ209L-hbER) in cardiac myocytes that can be activated by tamoxifen. Following drug treatment to activate Galpha q Q209L-hbER, these mice rapidly develop a dilated cardiomyopathy and heart failure. This phenotype does not appear to involve myocyte hypertrophy but is associated with dephosphorylation of phospholamban (PLB), decreased sarcoplasmic reticulum Ca2+-ATPase activity, and a decrease in L-type Ca2+ current density. Changes in Ca2+ handling and decreased cardiac contractility are apparent 1 week after Galpha qQ209L-hbER activation. In contrast, transgenic mice that express an inducible Galpha q mutant that cannot activate phospholipase Cbeta (PLCbeta) do not develop heart failure or changes in PLB phosphorylation, but do show decreased L-type Ca2+ current density. These results demonstrate that activation of Galpha q in cardiac myocytes of adult mice causes a dilated cardiomyopathy that requires the activation of PLCbeta. However, increased PLCbeta signaling is not required for all of the Galpha q-induced cardiac abnormalities.

Animals↗
PubMed1998

Contribution of virus-specific CD8+ cytotoxic T cells to virus clearance or pathologic manifestations of influenza virus infection in a T cell receptor transgenic mouse model.

The ability of influenza virus to evade immune surveillance by neutralizing antibodies (Abs) directed against its variable surface antigens provides a challenge to the development of effective vaccines. CD8+ cytotoxic T lymphocytes (CTLs) restricted by class I major histocompatibility complex molecules are important in establishing immunity to influenza virus because they recognize internal viral proteins which are conserved between multiple viral strains. In contrast, protective Abs are strain-specific. However, the precise role of effector CD8+ CTLs in protection from influenza virus infection, critical for understanding disease pathogenesis, has not been well defined. In transgenic mice with a very high frequency of antiinfluenza CTL precursors, but without protective Abs, CD8+ CTLs conferred protection against low dose viral challenge, but exacerbated viral pathology and caused mortality at high viral dose. The data suggest a dual role for CD8+ CTLs against influenza, which may present a challenge to the development of effective CTL vaccines. Effector mechanisms used by CD8+ CTLs in orchestrating clearance of virus and recovery from experimental influenza infection, or potentiation of lethal pathology, are discussed.

Animals↗