The Role of Thrombospondins in Atherothrombosis

血小板反应蛋白在动脉粥样硬化血栓形成中的作用

• 批准号: 6892786
• 负责人: EDWARD Franklin PLOW
• 金额: $ 19.13万
• 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: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892786
• 关键词: atherosclerosis; cardiovascular disorder risk; coronary disorder; disease /disorder model; gene expression; gene targeting; genetic susceptibility; genetically modified animals; human subject; laboratory mouse; medical complication; messenger RNA; myocardial infarction; patient oriented research; phenotype; protein structure; single nucleotide polymorphism; thrombospondins

In the post-genomic era, high through put genome-wide scans and SNP association studies hold the promise of identifying new genes as significant risk factors for coronary artery disease (CAD) and myocardial infarction (MI). Such information raises a new challenge: how does an identified gene product influence disease? This was the challenge that emerged from GeneQuest I. This large-scale SNP case-control study in patients with familial, premature CAD/MI identified three gene that exhibited a significant association with MI. All three were members of the thrombospondin (TSP) gene family. The remarkable clustering of genes within a single family strongly implicates the TSP family in cardiovascular pathology, and this link is further bolstered by the replication of the TSP-2 and TSP-4 associations with MI in separate clinical studies and our own preliminary data showing that each of the three TSP SNP set displays distinct functions. This project will focus on TSP-4 and TSP-2. In TSP-4, the SNP leads to a A387 P substitution, occurs at high frequency (34% in the Caucasian population), and increases the risk of MI by almost 2-fold. In TSP-2, the SNP is a t3943g substitution in the 3'-untranslated region, occurs with high frequent (10%) and is protective (approximately 3-fold reduction in MI). The hypothesis to be tested is: the SNPs in TSP-4 and TSP-2 alter protein (TSP-4) or mRNA (TSP-2) structure, which affects the function and/or expression of the TSPs. Such alterations affect the responses of vascular cells, creating a pro- or anti-atherogenic environment in the vessel wall. To test this hypotheses, we will: 1) examine the influence of the TSP-4 and TSP-2 SNPs at a molecular and cellular level; 2) explore murine atherosclerosis and vascular injury models in which expression of the TSPs has been altered; 3) examine normal and atherosclerotic human vessels for SNP-dependent changes in mRNA and protein; 4) determine if the SNP variants induce different gene profiles consistent with their atherogenic effects; and 5) exploit the GeneBank of cardiology patients to establish additional associations of the TSPs with MI. The aggregate of these studies should provide a rigorous test of the hypothesis, extend our knowledge of the TSPs in cardiovascular disease; provide insights into their structure and function; and define general approaches to examine oathozenic mechanisms of other gene products that are linked to CAD and MI.

在后基因组时代，高通量全基因组扫描和SNP关联研究有望识别新基因作为冠状动脉疾病（CAD）和心肌梗死（MI）的重要风险因素。这些信息提出了一个新的挑战：一个已确定的基因产物如何影响疾病？这就是GeneQuest I的挑战。这项针对家族性过早CAD/MI患者的大规模SNP病例对照研究确定了三个与MI显着相关的基因。这三个人都是血小板反应蛋白（TSP）基因家族的成员。单个家族内基因的显著聚集强烈暗示TSP家族与心血管病理学有关，并且在单独的临床研究中TSP-2和TSP-4与MI的关联的复制以及我们自己的初步数据显示三个TSP SNP集中的每一个显示不同的功能进一步支持了这种联系。该项目将侧重于TSP-4和TSP-2。在TSP-4中，SNP导致A387 P置换，发生频率很高（高加索人群中为34%），并使MI风险增加近2倍。在TSP-2中，SNP是3 '-非翻译区中的t3943 g取代，以高频率（10%）发生，并且是保护性的（MI降低约3倍）。待检验的假设是：TSP-4和TSP-2中的SNP改变蛋白质（TSP-4）或mRNA（TSP-2）结构，从而影响TSP的功能和/或表达。这种改变影响血管细胞的反应，在血管壁中产生促动脉粥样硬化或抗动脉粥样硬化的环境。为了验证这一假设，我们将：1）在分子和细胞水平上检测TSP-4和TSP-2 SNP的影响; 2）探索TSP表达改变的小鼠动脉粥样硬化和血管损伤模型; 3）检测正常和动脉粥样硬化的人血管中mRNA和蛋白质的SNP依赖性变化; 4）确定SNP变体是否诱导与其致动脉粥样硬化作用一致的不同基因谱;和5）利用心脏病患者的基因库来建立TSP与MI的额外关联。的 这些研究的集合应该提供对假设的严格检验，扩展我们对心血管疾病中TSP的知识;提供对它们的结构和功能的见解;并定义检查与CAD和MI相关的其他基因产物的臭氧机制的一般方法。