Genetic regulation of racial differences in platelet reactivity

血小板反应性种族差异的基因调控

• 批准号: 9011388
• 负责人: PAUL F. BRAY
• 金额: $ 38.75万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-09 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011388
• 关键词: 12-HETE; 14q32; Accounting; Address; Adverse effects; Arterial Fatty Streak; Automobile Driving; Biochemical; Biochemistry; Bioinformatics; Black race; Blood Platelets; Candidate Disease Gene; Cells; Cellular biology; Chromosomes; Clinical; Coronary artery; Coronary heart disease; CpG Islands; Critical Pathways; Data; Economics; Event; F2R gene; Fatty Acids; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Health; Human; Incidence; Kinetics; Lipids; Mediating; Megakaryocytes; Messenger RNA; MicroRNAs; Molecular; Molecular Genetics; Morbidity - disease rate; Movement; Myocardial Infarction; PAWR gene; Phospholipase A2; Physiological; Physiology; Platelet Activation; Platelet aggregation; Population; Process; Production; Protein Family; Proteins; Race; Regulation; Research Design; Role; Rupture; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stroke; System; Thrombin Receptor; Thrombosis; Thromboxanes; Thrombus; Time; Transcript; Variant; base; bisulfite; cohort; differential expression; high risk; imprint; mortality; novel; overexpression; personalized management; phosphatidylcholine transfer protein; protein complex; protein function; pyrosequencing; racial difference; racial disparity; receptor; release of sequestered calcium ion into cytoplasm; research study; rhoA GTP-Binding Protein; socioeconomics

DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is the most common killer in both whites and blacks. However, blacks have a 2- fold increase in the incidence of CHD as well as a lower long-term survival compared to whites. These differences cannot be fully explained by demographic, clinical, or economic confounders between these groups. As myocardial infarction and stroke typically result from an occlusive platelet thrombus formed at the site of a ruptured atherosclerotic plaque, understanding differences in the mechanisms by which platelets are activated in blacks and whites is expected to aid in our ability to optimally treat these populations following myocardial infarction (MI) and stroke. Our preliminary data demonstrates, for the first time, 1) racial differences in PAR4-mediated platelet aggregation, and 2) platelet mRNAs and microRNAs that are differentially expressed (DE) between blacks and whites and regulate PRA4 activation. The goals of this application are to characterize 1) the critical pathways and proteins responsible for these racial differences in platelet function, and 2 the molecular genetic basis for differences in gene expression. These goals will be addressed with physiology, biochemistry, genomic and cell biology approaches in human platelets and megakaryocytes. Aim 1 will dissect racial differences in platelet function using physiological and biochemical endpoints to assess PAR4 activation kinetics and absolute level of activity. By integrating the information attained in Aim 1, Aim 2 will evaluate novel candidate platelet genes DE expressed between blacks and whites. These genes will be characterized for their potential role in regulating the racial difference in PAR4-mediated reactivity of platelets. In particular, w find phosphatidylcholine transfer protein (PC-TP), is significantly higher in platelets from blacks compared to platelets from whites. PC-TP regulates lipid movement in the cell, a critical process in platelet activation. Several other strong candidate platelet genes - also DE by race - will also be characterized. Aim 3 will focus on novel mechanisms of gene expression that account for racial differences in platelet aggregation. We have identified the first example of miRNAs that are DE by race and by PAR4-mediated platelet aggregation. We will genetically manipulate candidate miRNAs in cultured human megakaryocytes to assess their effects on regulating PAR4-mediated platelet/megakaryocyte reactivity. We will also assess the molecular basis for the differential expression of miRNAs. This study will be the first to characterize racial differences in platelet activation at the signaling, protein and genetic levels. Understanding the racial difference in platelet activity will fill a significant gap in our understanding of why blacs suffer a higher morbidity and mortality than whites following MI and stroke.

描述（由申请人提供）：冠心病（CHD）是白人和黑人中最常见的杀手。然而，与白人相比，黑人的 CHD 发病率增加了 2 倍，且长期生存率较低。这些差异不能通过这些群体之间的人口统计学、临床或经济混杂因素来完全解释。由于心肌梗塞和中风通常是由动脉粥样硬化斑块破裂处形成的闭塞性血小板血栓引起的，因此了解黑人和白人血小板激活机制的差异有望有助于我们在心肌梗死后最佳地治疗这些人群的能力。梗塞（MI）和中风。我们的初步数据首次证明，1) PAR4 介导的血小板聚集存在种族差异，2) 黑人和白人之间差异表达 (DE) 并调节 PRA4 激活的血小板 mRNA 和 microRNA。本应用的目标是表征 1) 导致血小板功能种族差异的关键途径和蛋白质，以及 2 基因表达差异的分子遗传基础。这些目标将通过人类血小板和巨核细胞的生理学、生物化学、基因组和细胞生物学方法来实现。目标 1 将使用生理和生化终点来剖析血小板功能的种族差异，以评估 PAR4 激活动力学和绝对活性水平。通过整合目标 1 中获得的信息，目标 2 将评估黑人和白人之间表达的新候选血小板基因 DE。这些基因将因其在调节 PAR4 介导的血小板反应性的种族差异方面的潜在作用而被表征。特别是，我们发现黑人血小板中的磷脂酰胆碱转移蛋白（PC-TP）明显较高 与白人的血小板相比。 PC-TP 调节细胞内的脂质运动，这是血小板活化的关键过程。其他几个强大的候选血小板基因 - 也按种族 DE - 也将 被表征。目标 3 将重点关注解释血小板聚集种族差异的基因表达新机制。我们已经确定了第一个通过种族和 PAR4 介导的血小板聚集而 DE 的 miRNA 例子。我们将对培养的人类巨核细胞中的候选 miRNA 进行基因操作，以评估它们对调节 PAR4 介导的血小板/巨核细胞反应性的影响。我们还将评估 miRNA 差异表达的分子基础。这项研究将首次在信号、蛋白质和遗传水平上描述血小板激活的种族差异。了解血小板活性的种族差异将填补我们对为什么黑人在心肌梗死和中风后比白人发病率和死亡率更高的理解上的重大空白。