PAR mediated Rap 1 activation in platelets

PAR 介导血小板中 Rap 1 的激活

• 批准号: 7113603
• 负责人: MICHAEL Allan HOLINSTAT
• 金额: $ 4.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113603
• 关键词: PAR; mediated; Rap; activation; platelets

DESCRIPTION (provided by applicant): Thrombin, one of the most potent activators of platelets, works through activation of G protein-coupled protease receptors PAR-1 and PAR-4, which upon activation lead to increases in intracellular calcium, Rap1 activation and finally platelet aggregation, the PAR signaling system has been targeted as a site for inhibiting platelet activation because blocking PAR signaling is thought to be crucial in decreasing the risk to bleeding observed in other anti-platelet therapies. The aim of this research proposal is to identify how thrombin may differentially signal Rap1 mediated platelet activation. Since Rap1 has been implicated in thrombin-induced activation of platelets and may be a crucial mediator signaling inside-out activation of integrin receptor GPIIbllla as well as activating other downstream signaling pathways, I propose to investigate, through the use of specific PAR inhibitors and G protein minigenes, the differential signaling involved from the PAR receptors to Rap1, what this difference in signaling translates to in the form of level of platelet activation and by what means Rap1 is able to activate aggregation and/or secretion in platelets following thrombin, PAR-1 or PAR-4.

描述（申请人提供）：凝血酶是最有效的血小板活化剂之一，通过活化G蛋白偶联蛋白酶受体PAR-1和PAR-4起作用，其在活化后导致细胞内钙增加、Rap 1活化并最终导致血小板聚集，PAR信号传导系统已被作为抑制血小板活化的靶点，因为阻断PAR信号传导被认为在降低在其他抗血小板治疗中观察到的出血风险。 这项研究的目的是确定凝血酶如何差异信号Rap 1介导的血小板活化。由于Rap 1与凝血酶诱导的血小板活化有关，并且可能是整合素受体GPIIbllla由内而外活化以及激活其他下游信号通路的关键介质，因此我建议通过使用特异性PAR抑制剂和G蛋白小基因来研究PAR受体与Rap 1之间的差异信号传导，这种信号传导的差异转化为血小板活化水平的形式，以及Rap 1能够在凝血酶、PAR-1或PAR-4之后活化血小板中的聚集和/或分泌的方式。