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.

黑人患冠心病（CHD）的死亡率高于白人，甚至 调整了临床和人群混杂因素后。血小板反应性的提高与 增加脑部血小板形成的风险增加，这是与CHD相关死亡率的主要原因。血小板来自 与白人的血小板相比，黑人是多活跃的，响应于蛋白酶活化受体4（PAR4） 即使存在双重抗血小板治疗（DAPT），阿司匹林和P2Y12受体拮抗剂，刺激也是如此。 但是，尚不清楚PAR4介导的血小板激活中的种族差异是否导致 与白人相比，黑色的凝块形成增加。这项研究的长期目标是更好 了解PAR4介导的血小板反应性差异的根本原因并确定 PAR4激活的差异是否导致黑人相对于白人的血栓形成增加。到 AIM 1将重点放在描述负责PAR4信号种族差异的机制上。 候选人将获得技术专业知识，以研究PAR4中的多态性如何，更常见 黑色比白人调节PAR4激活（AIM 1的K99阶段）。 AIM 1的R00阶段将确定 PAR4激活的差异是否增强了下游信号传导，以及罕见的PAR4多态性 影响PAR4激活。此外，尚不清楚PAR4介导的血小板反应性的种族差异是否 DAPT的心脏患者的血小板持续。因此，在AIM 2的K99阶段，DAPT的患者将是 招募及其血小板反应性将被评估，以确定PAR4介导的种族差异是否存在 在DAPT上的个体中，血小板激活持续存在。 AIM 2的R00阶段将利用生成的生物座 在K99阶段，确定黑人与 白人。确定黑人和白人血栓形成之间是否有所不同 用人源化小鼠（AIM 3的K99相）以及离体模型（R00相； AIM 3）在体内评估。 此外，人性化鼠标模型将用于确定种族差异是否存在 止血（AIM 3的R00期）。更好地理解负责种族差异的机制 在PAR4中，信号传导将为有针对性的治疗提供证据，以治疗PAR4-的患者 介导的血小板反应性。此外，由于PAR1拮抗剂目前已被批准，PAR4拮抗剂是 在临床前开发中，这项工作具有重要的临床意义，即患者可能受益最多 从选择性的抑制作用。该建议描述了一个教学课程，研讨会， 和实践培训，将候选人与他的导师区分开来，并允许他发展 血小板差异研究的独立职业。