The racial disparity in platelet PAR4 signaling enhances thrombus formation

血小板 PAR4 信号传导的种族差异增强血栓形成

• 批准号: 10380592
• 负责人: Benjamin Eric Tourdot
• 金额: $ 24.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380592
• 关键词: Address; Affect; Allosteric Site; Aspirin; Binding; Binding Sites; Black Populations; Blood Platelets; Cardiac; Cardiovascular Diseases; Clinical; Coagulation Process; Coronary heart disease; Cytoplasmic Granules; Disease; Event; F2R gene; FDA approved; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Polymorphism; Goals; Hemostatic function; Human; Hyperactivity; Incidence; Individual; Kinetics; Mediating; Membrane; Mentors; Modeling; Mus; Pathology; Patients; Phase; Platelet Activation; Platelet aggregation; Plavix; Process; Race; Research; Risk; Role; Signal Pathway; Signal Transduction; Sodium; Technical Expertise; Testing; Thrombin; Thrombin Receptor; Thrombosis; Thrombus; Training; Variant; Whole Blood; Work; antagonist; atherosclerotic plaque rupture; base; biobank; black patient; career; genetic risk factor; humanized mouse; in vivo; inhibitor; mortality; mouse model; novel therapeutic intervention; preclinical development; protease-activated receptor 4; protein activation; racial difference; racial disparity; receptor; recruit; response; standard of care; targeted treatment; thrombotic

Black individuals have a higher mortality rate from coronary heart disease (CHD) than white individuals, even after adjusting for clinical and demographic confounders. Heightened platelet reactivity is associated with an increased risk for occlusive platelet-rich clot formation, the major cause of CHD-related mortality. Platelets from blacks were hyperactive compared to platelets from whites in response to protease activated receptor 4 (PAR4) stimulation even in the presence of dual antiplatelet therapy (DAPT), aspirin, and a P2Y12 receptor antagonist. However, it remains unknown whether the racial difference in PAR4-mediated platelet activation results in an increase in clot formation in blacks compared to whites. The long-term objective of this study is to better understand the underlying cause of the disparity in PAR4-mediated platelet reactivity and determine whether the difference in PAR4 activation leads to increased thrombosis in blacks relative to whites. To this end, Aim 1 will focus on delineating the mechanism responsible for the racial difference in PAR4 signaling. The candidate will acquire technical expertise in order to study how a polymorphism in PAR4, more common in blacks than whites, regulates PAR4 activation (K99 phase of Aim 1). The R00 phase of Aim 1 will determine whether differences in PAR4 activation enhance downstream signaling, and how rare PAR4 polymorphisms influence PAR4 activation. Further, it remains unknown if the racial disparity in PAR4-mediated platelet reactivity persists in platelets from cardiac patients on DAPT. Hence, in the K99 phase of Aim 2, patients on DAPT will be recruited and their platelet reactivity will be assessed to determine if the racial difference in PAR4-mediated platelet activation persists in individuals on DAPT. The R00 phase of Aim 2 will utilize a biorepository generated during the K99 phase to determine whether blacks have an increase in basal platelet activation compared to whites. To determine whether thrombosis differs between blacks and whites thrombus formation will be evaluated in vivo with humanized mouse (K99 phase of Aim 3), as well as ex vivo models (R00 phase; Aim 3). Additionally, humanized mouse models will be used to determine whether there is a racial difference in hemostasis (R00 phase of Aim 3). A better understanding of the mechanism responsible for the racial disparity in PAR4 signaling will provide evidence for targeted therapy to treat individuals with an increase in PAR4- mediated platelet reactivity. Additionally, as PAR1 antagonists are currently approved and PAR4 antagonists are in pre-clinical development, this work has important clinical implication as to which patients may benefit the most from selective PAR inhibition. This proposal describes an intensive training plan of didactic courses, seminars, and hands-on training that will differentiate the candidate from his mentor and allow him to develop an independent career in platelet disparities research.

黑人个体冠心病（CHD）的死亡率高于白色个体，甚至 在调整临床和人口统计学混杂因素后。血小板反应性升高与 闭塞性富血小板凝块形成的风险增加，这是CHD相关死亡的主要原因。血小板 与白人血小板相比，黑人血小板对蛋白酶激活受体4（PAR 4）的反应过度活跃 即使在双重抗血小板治疗（DAPT）、阿司匹林和P2 Y12受体拮抗剂存在下，也可以抑制血小板刺激。 然而，PAR 4介导的血小板活化的种族差异是否导致了血小板活化， 与白人相比，黑人的血凝块形成增加。这项研究的长期目标是更好地 了解PAR 4介导的血小板反应性差异的根本原因，并确定 PAR 4激活的差异是否导致黑人相对于白人血栓形成增加。到 为此，目标1将集中于阐明PAR 4信号传导中种族差异的机制。 候选人将获得技术专长，以研究如何在PAR 4多态性，更常见的是， 黑人比白人调节PAR 4活化（Aim 1的K99期）。目标1的R 00阶段将决定 PAR 4激活的差异是否增强下游信号传导，以及PAR 4多态性的罕见程度 影响PAR 4活化。此外，目前尚不清楚PAR 4介导的血小板反应性的种族差异是否 在接受DAPT的心脏病患者的血小板中持续存在。因此，在目标2的K99期，接受DAPT的患者将 招募并评估其血小板反应性，以确定PAR 4介导的血小板反应性的种族差异是否存在。 血小板活化在DAPT个体中持续存在。Aim 2的R 00阶段将利用生物储存库， 在K99阶段，以确定与对照组相比，黑人的基础血小板活化是否增加。 白人为了确定黑人和白人之间血栓形成是否不同， 用人源化小鼠（Aim 3的K99期）以及离体模型（R 00期; Aim 3）进行体内评价。 此外，将使用人源化小鼠模型来确定是否存在种族差异。 止血（目标3的R 00阶段）。更好地理解造成种族差异的机制 将为靶向治疗提供证据，以治疗PAR 4- 介导的血小板反应性。此外，由于PAR 1拮抗剂目前已获得批准，而PAR 4拮抗剂已获得批准 在临床前开发中，这项工作对于哪些患者可能受益最大具有重要的临床意义 选择性PAR抑制。该建议描述了一个教学课程，研讨会， 和实践培训，将区分候选人从他的导师，并让他发展一个 独立从事血小板差异研究。