ROLE OF PAR RECEPTORS IN HUMAN PLATELET FUNCTION

凝血酶是血小板最有效的激活剂，通过激活G蛋白偶联蛋白酶来激活血小板。 受体PAR 1和PAR 4。这些受体启动G蛋白信号级联，导致增加 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 例如比伐卢定在介入心脏病学中的使用迅速增加。然而，凝血酶的直接作用， 凝血，以及其通过凝血酶/血栓调节蛋白对血管系统的保护作用未被充分认识 蛋白质C的激活被这种策略阻断。另一种治疗靶点是PAR受体系统， 因为选择性阻断凝血酶的细胞信号作用可能会进一步降低出血风险。我们有 初步证据表明，与PAR 1相比，PAR 4的信号传导存在差异; 通过PAR 4受体由内而外的整合素信号传导、分泌和聚集的过程将被彻底地 在目标1中进行了研究。在目标2中，我们将确定PAR 4信号转导与新型G蛋白的分子基础 用于人血小板研究的阻断工具，每次一种，可抑制Gq、Gi、Go、G12或 通过PAR受体的G13信号传导。 虽然比伐卢定越来越多地用于急性冠脉护理，但凝血酶抑制剂对血小板的影响 功能尚未得到彻底研究。因此，我们提出了两个临床目的，比较血小板PAR 信号传导和血小板功能。在目标3中，我们将研究稳定或不稳定冠状动脉疾病患者。 在范德比尔特心脏试验中，将在比伐卢定给药前和给药期间研究其血小板PAR信号对血小板功能的影响。 导管插入实验室。第二个clinical.study旨在评估代谢综合征中的PAR信号传导， 糖尿病、动脉粥样硬化血栓形成事件高风险并发症。在目标4中，我们设计了一种临床 本研究旨在阐明PAR受体对这些血栓形成状态下异常血小板活化的作用。 这些关于人血小板PAR 1和PAR 4差异信号传导的详细机制研究，以及对血小板PAR 1和PAR 4差异信号传导的影响的研究， 比伐卢定对血小板功能的影响将有助于了解动脉粥样硬化血栓形成中的血小板活化， 可能影响未来的抗血小板治疗策略。

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.