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.

凝血酶是血小板的最有效的激活剂，通过激活G蛋白偶联蛋白酶激活而起作用 受体PAR1和PAR4。这些受体启动G蛋白信号传导级联反应导致增加 自分泌激活剂的细胞内钙和分泌，促进血小板聚集。直接凝血酶抑制剂 诸如Bivalirudin之类的介入心脏病学正在迅速增加。但是，凝血酶在 凝结及其通过凝血酶/血小板蛋白在脉管系统上的保护作用不足 蛋白C的激活被这种策略所阻断。替代治疗目标是PAR受体系统， 因为选择性阻断凝血酶的细胞信号效应可能会进一步降低出血风险。我们有 与PAR1相比，指向通过PAR4差异信号传导的初步证据；分子信号传导 通过PAR4受体的过程到内而外的整联蛋白信号传导，分泌和聚集将彻底进行 在AIM 1中进行了研究。在AIM 2中，我们将用新型G蛋白确定PAR4信号的分子基础 阻止用于研究人类血小板的工具，这些工具一次会抑制，一次激活GQ，GI，GO，G12或 G13通过PAR受体信号传导。 尽管双伏鲁丁蛋白越来越多地用于急性冠状动脉护理中，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，我们提出了两个临床目的，以比较血小板PAR 信号传导和血小板功能。在AIM 3中，我们将调查患有稳定或不稳定冠状动脉疾病的患者。 将在vanderbilt Cardiac中的Bivalirudin之前和期间研究它们的血小板PAR信号传导到血小板功能 导管实验室。第二个临床旨在评估代谢综合征和 糖尿病，疾病因动脉粥样硬化事件的高风险而复杂。在AIM 4中，我们设计了一个临床 研究旨在解决PAR受体对这些血小板状态异常血小板激活的贡献。 这些关于人血小板PAR1和PAR4差异信号传导的详细机械研究，以及对影响的研究 双伏鲁丁在血小板功能上的洞察力将洞悉动脉粥样硬化中的血小板激活，并具有 影响未来抗血小板治疗策略的潜力。