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Identification and study of the vascular disease gene at 9p21.3

9p21.3血管疾病基因的鉴定与研究

基本信息

批准号：
8467030
负责人：
THOMAS QUERTERMOUS
金额：
$ 58.85万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467030
关键词：
9p21 9p21.3 Abdominal Aortic Aneurysm African American Alleles Animal Model Animals Antisense RNA Apolipoprotein E Apoptosis Atherosclerosis Binding Biology Blood Vessels Candidate Disease Gene Cardiovascular Diseases Cell physiology Cells Chromosomes Chromosomes, Human, Pair 9 Coronary heart disease Cyclin-Dependent Kinase Inhibitor Gene DNA Development Disease Elements Ethnic group Functional RNA Genes Genetic Genetic Enhancer Element Genetic Risk Genetic Variation Genome Human Human Gene Mapping Human Genetics Human Genome In Vitro Intercistronic Region Investigation Knock-out Knockout Mice Laboratories Link Maps Mediating Messenger RNA Modeling Molecular Molecular Biology Molecular Models Mus Names Nature Pathway interactions Peripheral Vascular Diseases Positioning Attribute Process Proteins RNA-Protein Interaction Regulation Research Resources Risk Scientist Signal Pathway Signal Transduction Stroke Therapeutic Tissues Transcript Translating Untranslated Regions Variant Vascular Diseases Work base cell type density disorder risk experience gene function genome wide association study insight molecular modeling mouse model public health relevance racial and ethnic research study therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): As much as half of the risk for atherosclerotic coronary heart disease (CHD) is genetic in nature, and an unprecedented amount of resources have recently been directed at association-based studies employing high density genome-wide scanning to identify genetic variation associated with CHD. These studies have identified a single region of the genome as the most highly associated with disease in an intergenic segment of chromosome 9 at p21.3, the Chromosome 9p21.3 CHD-Associated Region (C9CAR). The attributable risk for CHD explained by variation in this locus has been estimated at 10-15%. In addition to CHD, variants at C9CAR have been associated with other vascular diseases, including abdominal aortic aneurysm, stroke, and peripheral vascular disease. Although additional human genetics mapping efforts are underway in this laboratory and others, it is unlikely that they will identify the causative variation or elucidate the biology underlying the risk associated with 9p21.3 variants. Further progress will require efforts with basic molecular biology and animal model approaches. While there are several genes in this region of 9p21.3, none have been clearly linked to the disease-associated variation, and the causative variation has not been defined. Compelling recent evidence now suggests that a cyclin-dependent kinase inhibitor gene, CDKN2B, and a non-coding antisense RNA in the CDKN2B locus named ANRIL, are the most likely candidate genes linked to the variation at 9p21.3. Studies proposed here will identify which of these two candidates is the related gene, the mechanism by which 9p21.3 variation alters the function of this gene, and the fundamental disease-related pathways that it in turn regulates. Experiments in Specific Aim 1 will investigate allelic expression imbalance between the alleles of CDKN2B and ANRIL, and link this imbalance to variation in these genes as well as the intergenic C9CAR region. These studies will identify the causative gene and localize cis-acting transcriptional regulatory sequences. Additional experiments in this aim will characterize putative enhancer elements at C9CAR, identify the transcription factors that bind these elements and provide insights into cell types and signaling pathways that mediate the risk associated with this region. Specific Aim 2 will employ targeted deletion of CDKN2B and other genes at 9p21.3 in the apoE null atherosclerosis mouse model to provide insights into the cellular and molecular aspects of disease risk. Finally, in Specific Aim 3, targeted in vitro studies will further investigate how CDKN2B or ANRIL regulate basic cell fate decisions in vascular cell types and contribute to atherosclerotic disease. This work will identify the causative gene at 9p21.3, and disease related upstream and downstream pathways for further study and therapeutic targeting.

描述（由申请人提供）：多达一半的动脉粥样硬化性冠心病（CHD）的风险本质上是遗传的，最近前所未有的大量资源被用于基于关联的研究，采用高密度全基因组扫描来识别与冠心病相关的遗传变异。这些研究已经确定了基因组中一个与疾病高度相关的区域，位于9号染色体p21.3的基因间片段，即染色体9p21.3冠心病相关区（C9CAR）。据估计，该基因座变异导致冠心病的归因风险为10-15%。除冠心病外，C9CAR的变异还与其他血管疾病有关，包括腹主动脉瘤、中风和周围血管疾病。尽管在这个实验室和其他实验室正在进行更多的人类遗传学测绘工作，但他们不太可能确定致病变异或阐明与9p21.3变异相关的生物学风险。进一步的进展将需要基础分子生物学和动物模型方法的努力。虽然在9p21.3的这个区域有几个基因，但没有一个与疾病相关的变异有明确的联系，致病变异也没有被定义。最近的有力证据表明，细胞周期蛋白依赖性激酶抑制剂基因CDKN2B和CDKN2B位点上名为ANRIL的非编码反义RNA是与9p21.3变异相关的最有可能的候选基因。这里提出的研究将确定这两个候选基因中的哪一个是相关基因，9p21.3变异改变该基因功能的机制，以及它反过来调节的基本疾病相关途径。Specific Aim 1中的实验将研究CDKN2B和ANRIL等位基因之间的等位基因表达失衡，并将这种失衡与这些基因以及基因间C9CAR区域的变异联系起来。这些研究将确定致病基因和定位顺式作用的转录调控序列。在此目标下的其他实验将表征C9CAR中假定的增强子元件，确定结合这些元件的转录因子，并提供对介导该区域相关风险的细胞类型和信号通路的见解。Specific Aim 2将在apoE缺失的动脉粥样硬化小鼠模型中靶向删除CDKN2B和其他9p21.3位点的基因，以深入了解疾病风险的细胞和分子方面。最后，在Specific Aim 3中，靶向体外研究将进一步研究CDKN2B或ANRIL如何调节血管细胞类型的基本细胞命运决定并促进动脉粥样硬化疾病。这项工作将确定9p21.3的致病基因，以及与疾病相关的上下游途径，为进一步研究和治疗靶向提供依据。