PAR mediated Rap 1 activation in platelets

描述（由申请人提供）：凝血酶是血小板最有效的激活剂之一，通过激活G蛋白偶联蛋白酶受体PAR-1和PAR-4起作用，激活后导致细胞内钙增加，Rap1激活并最终导致血小板聚集，PAR信号系统被认为是抑制血小板激活的一个位点，因为阻断PAR信号被认为是降低其他抗血小板治疗中观察到的出血风险的关键。

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.