Molecular Determinants of Coronary Artery Disease

描述（由申请人提供）： 我们对冠状动脉疾病（CAD）的病理生理学的理解已经取得了相当大的进展;然而，导致心血管疾病风险增加的遗传和分子决定因素仍然定义不清。本研究计划的主要目标是确定参与CAD及其主要并发症-急性心肌梗死（MI）发展的遗传和分子决定因素。为了实现这一目标，我们紧密团结，多学科和完全整合的团队将采用临床和转化研究相结合的方式，利用我们机构在心血管患者护理方面的优势。该研究计划分为4个相互关联的项目和5个服务于项目的核心，包括围绕基于家庭（GeneQuest）和基于人群（GeneBank）的临床队列构建的临床核心。项目1的目标是鉴定和表征导致早发CAD/MI的基因。初步数据包括从单个扩展谱系中发现MEF 2A基因中的一个功能突变，该突变与常染色体显性遗传的CAD有关，以及从428个患有早产儿CAD的多重家庭的全基因组扫描中鉴定出与早产儿MI有关的1号染色体上的一个位点（LOD评分>11）。我们建议描述这种特定的突变，收集更丰富的家系，并确定其他易患CAD/MI的基因。项目2的目标是确定负责近交系小鼠动脉粥样硬化易感性差异的基因，并确定这些基因的人类直系同源物中的遗传变异是否与CAD相关。初步数据包括通过计算机模拟方法鉴定的小鼠动脉粥样硬化易感基因位点，以及提示这些位点内的候选基因的基因阵列研究。项目3的目标源于我们对与MI相关的血小板反应蛋白（THBS）变体的新发现，旨在表征THBS-4和THBS-2中2种常见变体的细胞、分子和结构后果;以及评估这些THBS变体在患者中的后果。项目4的目标，基于广泛的髓过氧化物酶和NO衍生氧化剂与动脉粥样硬化性疾病的前期工作，是研究氧化应激，逆转胆固醇转运的影响，以及新发现的这些途径之间的相互联系对冠状动脉粥样硬化进展/消退的患者。支持这些项目的5个核心是1）管理，2）生物信息学和生物统计学，3）基因表达，测序和基因分型，4）临床基础设施，5）临床研究技能和发展。我们集体工作的成果应当对今后冠状动脉疾病的预防、诊断和治疗产生重大影响。

DESCRIPTION (provided by applicant): Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD); however, the genetic and molecular determinants that predispose to enhanced risk for cardiovascular disease remain poorly defined. The primary goal of this Research Program is to identify genetic and molecular determinants that participate in the development of CAD and its major complication - acute myocardial infarction (MI). To achieve this goal, our close-knit, multidisciplinary, and fully integrated team will employ a combination of clinical and translational studies that draw upon our institution's strength in cardiovascular patient care. The Research Program is structured into 4 interrelated Projects and 5 Cores that serve the Projects, including a Clinical Core built around a family based (GeneQuest) and a population based (GeneBank) clinical cohort. The goals of Project 1 are to identify and characterize genes that lead to premature CAD/MI. Preliminary data include the discovery, from a single extended pedigree, of a functional mutation in the MEF2A gene that is linked to autosomal dominantly inherited CAD, and the identification of a locus on chromosome 1 that is linked to premature MI (LOD score >11), from a genome-wide scan of 428 multiplex families with premature CAD. We propose to characterize this specific mutation, assemble more rich pedigrees, and identify additional genes that predispose to CAD/MI. The goals of Project 2 are to identify the genes responsible for the differences in atherosclerosis susceptibility among inbred strains of mice, and to determine if genetic variation in the human orthologs of these genes are associated with CAD. Preliminary data include murine atherosclerosis susceptibility loci identified through an in silico method, and gene array studies that suggest candidate genes within these loci. The goals of Project 3, originating from our novel finding of thrombospondin (THBS) variants associated with MI, are to characterize the cellular, molecular and structural consequences of 2 common variants in THBS-4 and THBS-2; and, the assessment of the consequences of these THBS variants in patients. The goals of Project 4, based upon extensive prior work in myeloperoxidase and NO-derived oxidants linked to atherosclerotic disease, are to investigate the of implications of oxidant stress, reverse cholesterol transport, and newly identified interconnections between these pathways on coronary atherosclerotic progression/regression in patients. The 5 Cores that support these projects are for 1) Administration, 2) Bioinformatics and biostatistics, 3) Gene expression, sequencing and genotyping, 4) Clinical infrastructure, and 5) Clinical research skills and development. The output from our collective work should have a significant impact on prevention, diagnosis and treatment of coronary artery disease in the future.