PROTEASE ACTIVATED RECEPTOR 3

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DESCRIPTION: Thrombin is a multifunctional serine protease generated at sites of vascular injury. Its in vitro actions on platelets, leukocytes, endothelial and mesenchymal cells suggest that thrombin may mediate not only hemostasis and thrombosis but also inflammatory and proliferative responses to vascular damage in vivo. The overall goal of the application is to understand thrombin signaling, thereby providing strategies to prevent unwanted responses to vascular injury such as formation of platelet thrombi overlying ruptured atherosclerotic plaques, the usual cause of unstable angina and myocardial infarction. Knockout of par1, the first thrombin receptor cloned and characterized by the investigator s group, provided definitive evidence for the existence of second thrombin receptor in mouse platelets and for tissue specific roles for distinct thrombin receptors. Dr. Coughlin recently cloned and characterized par3, a second thrombin receptor that is expressed in human bone marrow and mouse megakaryocytes. The proposal seeks to define the role of par3 in vivo and the signaling mechanisms that it utilizes. The investigator seeks to answer the following questions: What are the roles of par1 and par3 in human platelets and other cells? Does par3 account for thrombin signaling in par1 -/- mouse platelets or do still other thrombin receptors exist? Are the signaling mechanisms utilized by par3 distinct from those used by par1, and what is the signaling pathway from par3 activation to platelet secretion and aggregation?