Genetic regulation of racial differences in platelet reactivity

描述（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，黑人的冠心病发病率增加了2倍，长期存活率也较低。这些差异不能完全用人口统计学、临床或经济混杂因素来解释。由于心肌梗死和中风通常是由动脉粥样硬化斑块破裂部位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帮助我们优化心肌梗死和中风后这些人群的治疗。我们的初步数据首次表明，1)par4介导的血小板聚集存在种族差异，2)黑人和白人之间的血小板mrna和microrna差异表达（DE）并调节PRA4的激活。该应用程序的目标是表征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。这些目标将解决生理学，生物化学，基因组学和细胞生物学方法在人类血小板和巨核细胞。目的1将使用生理和生化终点分析血小板功能的种族差异，以评估PAR4的激活动力学和绝对活性水平。通过整合Aim 1中获得的信息，Aim 2将评估黑人和白人之间表达的新的候选血小板基因DE。这些基因的特征在于它们在调节par4介导的血小板反应性的种族差异中的潜在作用。特别是，我们发现磷脂酰胆碱转移蛋白（PC-TP）在黑人血小板中明显较高

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.