ROLE OF PAR RECEPTORS IN HUMAN PLATELET FUNCTION

PAR 受体在人类血小板功能中的作用

• 批准号: 7250519
• 负责人: HEIDI E HAMM
• 金额: $ 39.67万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-20 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250519
• 关键词: CD40 molecule; G protein; biological signal transduction; blocking antibody; calcium flux; cellular pathology; coronary disorder; disease /disorder etiology; flow cytometry; heart catheterization; high performance liquid chromatography; hirudins; human subject; insulin sensitivity /resistance; integrins; metabolic syndrome; molecular pathology; noninsulin dependent diabetes mellitus; patient oriented research; peptide chemical synthesis; platelet activation; platelet aggregation; protein structure function; selectins; thrombin; thrombin receptor; thrombosis

Thrombin, the most potent activator of platelets, works by activation of the G protein-coupled protease activated receptors PAR1 and PAR4. These receptors initiate G protein signaling cascades leading to increases in intracellular calcium and secretion of autocrine activators, promoting platelet aggregation. Direct thrombin inhibitors such as bivalirudin are rapidly increasing in use in interventional cardiology. However, thrombin's direct role in coagulation, as well as its underappreciated protective role on the vasculature through the thrombin/thrombomodulin activation of Protein C, are blocked by this strategy. An alternate therapeutic target is the PAR receptor system, because selective blockade of thrombin's cellular signaling effects might further decrease bleeding risk. We have preliminary evidence that points to differential signaling through PAR4 compared to PAR1; the molecular signaling process through PAR4 receptors to inside-out integrin signaling, secretion and aggregation will be thoroughly investigated in Aim 1. In Aim 2, we will determine the molecular basis of PAR4 signaling with novel G protein blocking tools designed for studies in human platelets that will inhibit, one at a time, activation of Gq, Gi, Go, G12 or G13 signaling through PAR receptors. Although bivalirudin is increasingly used in acute coronary care, the effect of thrombin inhibition on platelet function has not been thoroughly investigated. Thus we propose two clinical aims to compare platelet PAR signaling and platelet function. In Aim 3, we will investigate patients with stable or unstable coronary artery disease. Their platelet PAR signaling to platelet function will be studied before and during bivalirudin in the Vanderbilt Cardiac Catheterization Laboratory. The second clinical.study aims to evaluate PAR signaling in metabolic syndrome and diabetes, conditions complicated by a high risk of atherothrombotic events. In Aim 4, we have designed a clinical study to address the contribution of PAR receptors to the abnormal platelet activation in these thrombotic states. These detailed mechanistic studies on human platelet PAR1 and PAR4 differential signaling, and studies on effects of bivalirudin on platelet function will provide insight into platelet activation in atherothrombosis, and has the potential to impact future antiplatelet therapeutic strategies.

凝血酶是最有效的血小板激活剂，通过激活 G 蛋白偶联蛋白酶来发挥作用 受体 PAR1 和 PAR4。这些受体启动 G 蛋白信号级联反应，导致 细胞内钙和自分泌激活剂的分泌，促进血小板聚集。直接凝血酶抑制剂 比伐卢定等药物在介入心脏病学中的应用正在迅速增加。然而，凝血酶的直接作用是 凝血，以及其通过凝血酶/血栓调节蛋白对脉管系统的未被充分认识的保护作用 蛋白 C 的激活被该策略阻断。另一个治疗靶点是 PAR 受体系统， 因为选择性阻断凝血酶的细胞信号传导效应可能会进一步降低出血风险。我们有 初步证据表明，与 PAR1 相比，PAR4 的信号传导存在差异；分子信号传导 通过 PAR4 受体进行由内而外的整合素信号传导、分泌和聚集的过程将彻底 在目标 1 中进行了研究。在目标 2 中，我们将利用新型 G 蛋白确定 PAR4 信号传导的分子基础 专为人类血小板研究而设计的阻断工具，可一次抑制一个 Gq、Gi、Go、G12 或 通过 PAR 受体的 G13 信号传导。 尽管比伐卢定越来越多地用于急性冠心病治疗，但凝血酶抑制对血小板的影响 功能尚未得到彻底研究。因此，我们提出两个临床目标来比较血小板 PAR 信号传导和血小板功能。在目标 3 中，我们将调查患有稳定或不稳定冠状动脉疾病的患者。 他们的血小板 PAR 信号对血小板功能的影响将在比伐卢定之前和期间在范德比尔特心脏中心进行研究 导管插入实验室。第二项临床研究旨在评估代谢综合征中的 PAR 信号传导 糖尿病，并发动脉粥样硬化血栓事件高风险的疾病。在目标 4 中，我们设计了一个临床 研究旨在解决 PAR 受体对这些血栓状态下异常血小板活化的影响。 这些关于人血小板 PAR1 和 PAR4 差异信号传导的详细机制研究以及影响研究 比伐卢定对血小板功能的影响将有助于深入了解动脉粥样硬化血栓形成中的血小板活化，并具有 可能影响未来的抗血小板治疗策略。