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: 10091614
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091614
• 关键词: Address; Affect; Allosteric Site; Aspirin; Binding; Binding Sites; 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; Hyperactive behavior; 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; atherosclerotic plaque rupture; base; biobank; career; genetic risk factor; humanized mouse; in vivo; inhibitor/antagonist; 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

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.

黑人因冠心病 (CHD) 死亡率高于白人，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 富含血小板的闭塞性血块形成的风险增加，这是冠心病相关死亡的主要原因。血小板来自 与白人相比，黑人的血小板对蛋白酶激活受体 4 (PAR4) 的反应过度活跃 即使在双重抗血小板治疗 (DAPT)、阿司匹林和 P2Y12 受体拮抗剂存在的情况下也能产生刺激。 然而，目前尚不清楚 PAR4 介导的血小板活化的种族差异是否会导致 与白人相比，黑人的血栓形成增加。本研究的长期目标是更好地 了解 PAR4 介导的血小板反应性差异的根本原因并确定 PAR4 激活的差异是否会导致黑人相对于白人的血栓形成增加。到 为此，目标 1 将重点描述 PAR4 信号传导种族差异的机制。 候选人将获得技术专业知识，以研究 PAR4 中的多态性（更常见于 黑人比白人更能调节 PAR4 激活（目标 1 的 K99 阶段）。目标 1 的 R00 阶段将决定 PAR4 激活的差异是否会增强下游信号传导，以及 PAR4 多态性如何罕见 影响 PAR4 的激活。此外，尚不清楚 PAR4 介导的血小板反应性是否存在种族差异 接受 DAPT 治疗的心脏病患者的血小板中持续存在。因此，在目标 2 的 K99 阶段，接受 DAPT 的患者将 招募并评估他们的血小板反应性，以确定 PAR4 介导的种族差异是否存在 接受 DAPT 治疗的个体中血小板活化持续存在。 Aim 2 的 R00 阶段将利用生成的生物存储库 在 K99 阶段，以确定黑人与黑人相比，基础血小板活化是否有所增加 白人。为了确定黑人和白人之间的血栓形成是否不同，血栓形成将 使用人源化小鼠（Aim 3 的 K99 相）以及离体模型（R00 相；Aim 3）进行体内评估。 此外，人源化小鼠模型将用于确定是否存在种族差异 止血（目标 3 的 R00 阶段）。更好地理解造成种族差异的机制 PAR4 信号传导的研究将为靶向治疗提供证据，以治疗 PAR4- 增加的个体 介导的血小板反应性。此外，由于 PAR1 拮抗剂目前已获批准，而 PAR4 拮抗剂也正在批准中。 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 来自选择性 PAR 抑制。该提案描述了教学课程、研讨会、 以及实践培训，使候选人有别于他的导师，并让他能够发展 血小板差异研究的独立职业。