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：
7937672
负责人：
THOMAS QUERTERMOUS
金额：
$ 61.89万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937672
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 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 Mus Names Nature Pathway interactions Peripheral Vascular Diseases Positioning Attribute Process Proteins RNA-Protein Interaction Regulation Research Resources Risk Scientist Signal Pathway 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 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. PUBLIC HEALTH RELEVANCE: Significant expense and effort by groups of scientists around the world has led to identification of regions of the human genome that are associated with the genetic risk for various forms of cardiovascular disease. Additional research is required to understand the specific genes involved, and how they work to contribute to the disease process. Such information will allow the development of better therapeutics for these diseases.

描述（由申请人提供）：多达一半的动脉粥样硬化性冠心病（CHD）风险本质上是遗传性的，并且最近有大量资源用于基于关联的研究，这些研究采用高密度全基因组扫描来识别与 CHD 相关的遗传变异。这些研究已确定基因组中与疾病最相关的单个区域，位于 9 号染色体 p21.3 的基因间片段，即染色体 9p21.3 CHD 相关区域 (C9CAR)。据估计，由该位点变异解释的 CHD 归因风险为 10-15%。除冠心病外，C9CAR 的变异还与其他血管疾病相关，包括腹主动脉瘤、中风和外周血管疾病。尽管该实验室和其他实验室正在进行更多的人类遗传学绘图工作，但他们不太可能识别致病变异或阐明与 9p21.3 变异相关的风险背后的生物学原理。进一步的进展需要基础分子生物学和动物模型方法的努力。虽然 9p21.3 的该区域有多个基因，但没有一个基因与疾病相关变异明确相关，并且致病变异尚未确定。最近令人信服的证据表明，细胞周期蛋白依赖性激酶抑制剂基因 CDKN2B 和 CDKN2B 基因座中名为 ANRIL 的非编码反义 RNA 是最有可能与 9p21.3 变异相关的候选基因。这里提出的研究将确定这两个候选基因中哪一个是相关基因、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。具体目标 1 中的实验将研究 CDKN2B 和 ANRIL 等位基因之间的等位基因表达不平衡，并将这种不平衡与这些基因以及基因间 C9CAR 区域的变异联系起来。这些研究将鉴定致病基因并定位顺式作用转录调控序列。此目的的其他实验将表征 C9CAR 上假定的增强子元件，识别结合这些元件的转录因子，并深入了解介导与该区域相关的风险的细胞类型和信号通路。具体目标 2 将在 apoE 缺失动脉粥样硬化小鼠模型中在 9p21.3 处定向删除 CDKN2B 和其他基因，以提供对疾病风险的细胞和分子方面的见解。最后，在具体目标 3 中，有针对性的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导致动脉粥样硬化疾病。这项工作将确定 9p21.3 的致病基因以及疾病相关的上游和下游途径，以供进一步研究和治疗靶向。公共卫生相关性：世界各地的科学家小组投入了大量费用和努力，确定了与各种形式的心血管疾病的遗传风险相关的人类基因组区域。需要进行更多的研究来了解所涉及的特定基因，以及它们如何促进疾病过程。这些信息将有助于开发出更好的治疗方法来治疗这些疾病。