Genetic Regulation of Arterial Wall by Canonical Wnt Signaling

典型 Wnt 信号传导对动脉壁的遗传调控

基本信息

批准号：
8828292
负责人：
Arya Mani
金额：
$ 53.3万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828292
关键词：
Accounting Address Alleles Aorta Arteries Blood Vessels Bone Marrow Cause of Death Cells Chimera organism Cholesterol Chromosome Mapping Clinical Research Coronary Arteriosclerosis Coronary artery Development Diabetes Mellitus Diet Diffuse Disease Disease Pathway Drug Targeting Endothelial Cells Engineering Epidemiologic Studies Fatty acid glycerol esters Functional disorder Gene Expression Profile Gene Silencing General Population Generations Genes Genetic Growth Factor Health Homozygote Human Hyperlipidemia Hyperplasia Hypertension In Vitro Insulin Resistance Ligand Binding Link MYH11 gene Maps Mediator of activation protein Mesenchymal Stem Cells Metabolic syndrome Metabolism Modeling Mus Mutation Nuclear Online Mendelian Inheritance In Man PDGF-AA PDGFRB gene Pathogenesis Pathway interactions Phenocopy Phenotype Phosphorylation Plasma Platelet-Derived Growth Factor Population Process Production Regulation Reporter Risk Factors Role Science Series Severities Signal Transduction Sorting - Cell Movement Source TCF7L2 gene Tissues Undifferentiated United States Variant Vascular Proliferation Vascular Smooth Muscle abstracting ascending aorta base beta catenin cardiovascular risk factor disease mechanisms study disorder control disorder risk early onset homologous recombination kindred lipoprotein receptor-related protein 6 loss of function mutation mortality mouse model mutant mutation carrier neointima formation novel overexpression physical property platelet-derived growth factor BB promoter research study response

Accounting Address Alleles Aorta Arteries Blood Vessels Bone Marrow Cause of Death Cells Chimera organism Cholesterol Chromosome Mapping Clinical Research Coronary Arteriosclerosis Coronary artery Development Diabetes Mellitus Diet Diffuse Disease Disease Pathway Drug Targeting Endothelial Cells Engineering Epidemiologic Studies Fatty acid glycerol esters Functional disorder Gene Expression Profile Gene Silencing General Population Generations Genes Genetic Growth Factor Health Homozygote Human Hyperlipidemia Hyperplasia Hypertension In Vitro Insulin Resistance Ligand Binding Link MYH11 gene Maps Mediator of activation protein Mesenchymal Stem Cells Metabolic syndrome Metabolism Modeling Mus Mutation Nuclear Online Mendelian Inheritance In Man PDGF-AA PDGFRB gene Pathogenesis Pathway interactions Phenocopy Phenotype Phosphorylation Plasma Platelet-Derived Growth Factor Population Process Production Regulation Reporter Risk Factors Role Science Series Severities Signal Transduction Sorting - Cell Movement Source TCF7L2 gene Tissues Undifferentiated United States Variant Vascular Proliferation Vascular Smooth Muscle abstracting ascending aorta base beta catenin cardiovascular risk factor disease mechanisms study disorder control disorder risk early onset homologous recombination kindred lipoprotein receptor-related protein 6 loss of function mutation mortality mouse model mutant mutation carrier neointima formation novel overexpression physical property platelet-derived growth factor BB promoter research study response

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项目摘要

DESCRIPTION (provided by applicant): Abstract: Coronary artery disease (CAD) and its consequences remain the single largest cause of death in the United States. Epidemiologic studies have established the key roles of several risk factors for coronary artery disease (CAD). However, there is significant overlap in extent and severity of established CAD risk factors between disease and control populations. This suggests that the disease in the general population cannot be accounted for by these risk factors alone and leaves open the question of how to identify novel risk factors. Through a series of studies, we recently identified a loss of function mutation in the Wnt co-receptor LRP6 (LRP6R611C) that underlies a Mendelian form of coronary artery disease, diabetes and metabolic syndrome. The characterization of the mutation has shown that it impairs ligand binding, reduces LRP6 phosphorylation and nuclear beta-catenin localization in response to Wnt stimulation, and subsequently impairs downstream Wnt signaling. Since our initial discovery, impaired Wnt signaling has shown to be a risk factor for CAD in multiple clinical and experimental studies. Discovery of this disease gene and its link to altered canonical Wnt signaling has provided an exceptional opportunity for identification of novel disease pathways. Through homologous recombination, we have generated mice with the LRP6R611C mutation. LRP6R611C mice replicate most human phenotypes, including arterial intimal hyperplasia on high fat diet and develop extremely diffuse and proliferative CAD when they are homozygote for the disease allele. We propose ( 1) to determine the origin of the neointimal cell (2) to examine the role of "canonical" Wnt/ß-catenin signaling in neointima formation and (3) to assess the contribution of bone marrow derived cells (BMD) to neointima formation, by fate mapping, genetic rescue and generation of bone marrow chimeras.

描述（由申请人提供）：摘要：冠状动脉疾病（CAD）及其后果仍然是美国最大的死亡原因。流行病学研究确定了冠状动脉疾病（CAD）的几种危险因素的关键作用。但是，疾病和对照人群之间已建立的CAD危险因素的程度和严重程度有显着重叠。这表明，仅这些危险因素无法解释普通人群中的疾病，并留下了如何识别新风险因素的问题。通过一系列研究，我们最近确定了Wnt共受体LRP6（LRP6R611C）中功能突变的丧失，该冠状动脉疾病，糖尿病和代谢综合征是Mendelian形式的基础。该突变的表征表明，它会损害配体结合，减少LRP6磷酸化和核β-catenin的定位，以响应Wnt刺激，然后损害下游Wnt信号传导。自我们最初发现以来，Wnt信号受损已显示为在多个临床和实验研究中CAD的危险因素。发现该疾病基因及其与改变的规范WNT信号的联系为鉴定新型疾病途径的出色机会提供了极大的机会。通过同源重组，我们与LRP6R611c突变产生了小鼠。 LRP6R611C小鼠复制了大多数人类表型，包括高脂饮食上的内膜增生，并在疾病等位基因纯合时产生极度扩散和增殖的CAD。我们建议（1）确定新内膜细胞（2）的起源（以检查“规范” Wnt/ß-catenin信号在新内膜形成中的作用，以及（3）通过脂肪映射，遗传救援和产生骨骼骨髓果肉来评估骨髓衍生细胞（BMD）对新内膜形成的贡献。