PAR mediated Rap 1 activation in platelets

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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.