Molecular Determinants of Coronary Artery Disease

冠状动脉疾病的分子决定因素

• 批准号: 7564814
• 负责人: EDWARD Franklin PLOW
• 金额: $ 350.45万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-09 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564814
• 关键词: Molecular; Determinants; Coronary; Artery; Disease

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.

描述（由申请人提供）： 在我们对冠状动脉疾病（CAD）的病理生理学的理解中，取得了长足的进步。但是，易于增强心血管疾病风险的遗传和分子决定因素仍然很差。该研究计划的主要目的是确定参与CAD发展及其主要并发症的遗传和分子决定因素 - 急性心肌梗塞（MI）。为了实现这一目标，我们的紧密联系，多学科和完全整合的团队将采用临床和转化研究的结合，借鉴我们机构在心血管患者护理中的实力。该研究计划构成了4个相互关联的项目和5个为项目提供服务的核心，包括围绕家庭（Genequest）和基于人群（Genebank）临床人群建立的临床核心。项目1的目标是识别和表征导致过早CAD/MI的基因。初步数据包括从单个扩展血统，MEF2A基因中功能突变的发现，该突变与常染色体相关，该发现与常染色体相关，并鉴定了1号染色体上的基因座，该基因座与Formature Mi（LOD分数> 11）相关，来自428个基因组WIDE-WIDE SCAN，来自428个倍增型号。我们建议表征这种特定的突变，组装更多丰富的血统，并确定易于CAD/MI的其他基因。项目2的目标是确定导致小鼠近交菌株动脉粥样硬化易感性差异的基因，并确定这些基因人类直系同源物的遗传变异是否与CAD相关。初步数据包括通过计算机方法鉴定的鼠动脉粥样硬化易感性基因座和基因阵列研究，这些研究表明这些基因座中的候选基因。项目3的目标源自与MI相关的新型血小板素（THB）变体的发现，是为了表征THBS-4和THBS-2中2种常见变体的细胞，分子和结构性后果。并且，评估患者这些THB的后果。项目4的目标是基于与动脉粥样硬化疾病相关的髓过氧化物酶和无衍生氧化剂的大量先前工作，是为了研究氧化剂应激，反向胆固醇转运的含义，以及新确定的患者冠状动脉粥样硬化进展/回归中这些途径之间的互连。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）临床基础设施以及5）临床研究技能和发展。我们的集体工作的产量应对未来的预防，诊断和治疗产生重大影响。

项目成果

Simon Dack Lecture. The genomic basis of myocardial infarction.

西蒙·达克讲座。

• DOI: 10.1016/j.jacc.2005.06.064
• 发表时间: 2005
• 期刊: Journal of the American College of Cardiology.
• 作者: Topol,EricJ

Changes in whole blood gene expression in obese subjects with type 2 diabetes following bariatric surgery: a pilot study.

• DOI: 10.1371/journal.pone.0016729
• 发表时间: 2011-03-10
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Berisha SZ;Serre D;Schauer P;Kashyap SR;Smith JD
• 通讯作者: Smith JD

Thrombospondins: old players, new games.

• DOI: 10.1097/mol.0b013e3283642912
• 发表时间: 2013-10
• 期刊: Current opinion in lipidology
• 影响因子: 4.4
• 作者: Stenina-Adognravi O

Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk.

• DOI: 10.1016/j.jacc.2009.02.036
• 发表时间: 2009-06-02
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Tang, W. H. Wilson;Wang, Zeneng;Cho, Leslie;Brennan, Danielle M.;Hazen, Stanley L.
• 通讯作者: Hazen, Stanley L.

Counterbalancing forces: what is thrombospondin-1 doing in atherosclerotic lesions?

平衡力：血小板反应蛋白-1 在动脉粥样硬化病变中有何作用？

• DOI: 10.1161/circresaha.108.188870
• 发表时间: 2008
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Stenina,OlgaI;Plow,EdwardF
• 通讯作者: Plow,EdwardF