Pharmacogenomics studies of PAR4 regulation in human platelets

人血小板 PAR4 调节的药物基因组学研究

基本信息

批准号：
8960415
负责人：
Benjamin Eric Tourdot
金额：
$ 5.42万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960415
关键词：
Address Affinity Aspirin Binding Biochemical Blood Platelets Bypass Cardiac Cardiology Cause of Death Clinical Coronary heart disease Cytoplasmic Granules Data Development Disease Event Exhibits F2R gene Functional disorder Genetic Genetic Polymorphism Genetic Variation Genotype Heterotrimeric GTP-Binding Proteins Human Individual Ligand Binding Ligand Binding Domain Ligands Mediating Myocardial Infarction Pathway interactions Patients Peptides Pharmacogenomics Platelet Activation Platelet aggregation Plavix Play Population Race Recruitment Activity Regulation Resistance Risk Role Signal Transduction Stroke Testing Thrombin Thrombin Receptor Thrombosis United States Variant Work cell type cyclooxygenase 1 design high risk inhibitor/antagonist new therapeutic target pre-clinical protease-activated receptor 4 public health relevance racial difference racial disparity receptor response socioeconomics standard of care targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Blacks are at an increased risk of myocardial infarction and stroke, two diseases with strong thrombotic components, compared to whites even after adjusting for socioeconomic and clinical confounders. Recent work in our group suggests that racial differences in the risk for a thrombotic event is at least in part due to geneic polymorphisms in the thrombin receptor, protease-activated receptor 4 (PAR4). Our preliminary data demonstrates that independent of race individuals homozygous for the T120 variant of PAR4 have an increase in PAR4-mediated platelet reactivity compared to individuals homozygous for the A120 variant. Additionally, this variant dependent activation of PAR4 persists in platelets treated ex vivo with COX and P2Y12 antagonists. To further delineate how the PAR4 variant influences platelet reactivity we propose to characterize the mechanism by which the T120A PAR4 variant increases PAR4-mediated platelet reactivity and determine if this variant alters platelet reactivity in the presence of current antiplatelet therapy. To this end, Ai 1 will address the mechanism by which the PAR4 T120 variant increases PAR4-mediated platelet reactivity by analyzing the biochemical components of the Gq and G12/13 pathways in PAR4 stimulated platelets isolated from donors expressing either variant. Additionally, it remains unknown if the PAR4 T120A substitution enhances PAR4-mediated platelet reactivity in platelets from cardiac patients on dual antiplatelet therapy. Hence, in Aim 2 we will recruit patients on dual antiplatelet that are homozygous for either variant to assess their platelet reactivity to determine if platelets isolated from individuals expressing T120 have an increase in PAR4-mediated platelet activation compared to platelets from individuals expressing A120. Finally, our preliminary data suggests that PAR4 is a new target for decreasing thrombotic events in patients with the T120 PAR4 variant. Therefore, in Aim 3 we will test the function of PAR4 antagonists to inhibit platelet activation of subjects independent of PAR4 variant. A further understanding of the mechanism by which the PAR4 variants enhance platelet reactivity will provide evidence for targeted therapy to treat those with an increase in PAR4 platelet reactivity.

描述（由申请人提供）：即使在调整了社会经济和临床混杂因素后，黑人患心肌梗塞和中风这两种具有强烈血栓成分的疾病的风险也会增加，即使在调整了社会经济和临床混杂因素后，黑人患心肌梗塞和中风的风险也增加。血栓事件的发生至少部分是由于凝血酶受体、蛋白酶激活受体 4 (PAR4) 的遗传多态性造成的。我们的初步数据表明，与种族个体无关的纯合子。与 A120 变体纯合个体相比，PAR4 的 T120 变体的 PAR4 介导的血小板反应性增加。此外，这种 PAR4 的变体依赖性激活在用 COX 和 P2Y12 拮抗剂离体处理的血小板中持续存在。变异影响血小板反应性我们建议描述 T120A PAR4 变异增加 PAR4 介导的血小板反应性的机制，并确定该变异是否在当前抗血小板治疗的情况下改变血小板反应性为此，Ai 1 将通过分析 PAR4 刺激的血小板中 Gq 和 G12/13 途径的生化成分来探讨 PAR4 T120 变体增加 PAR4 介导的血小板反应性的机制。此外，目前尚不清楚 PAR4 T120A 替代是否会增强心脏病患者血小板中 PAR4 介导的血小板反应性。因此，在目标 2 中，我们将招募任一变体纯合的双重抗血小板患者来评估他们的血小板反应性，以确定与表达 A120 的个体的血小板相比，从表达 T120 分离的血小板是否具有 PAR4 介导的血小板活化增加。最后，我们的初步数据表明 PAR4 是减少 T120 PAR4 变异患者血栓事件的新靶标，因此，在目标 3 中我们将测试该功能。 PAR4拮抗剂抑制受试者血小板活化的研究与PAR4变体无关。进一步了解PAR4变体增强血小板反应性的机制将为靶向治疗治疗PAR4血小板反应性增加的患者提供证据。