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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.