Our laboratory seeks to understand signaling mechanisms underlying cardiovascular biology and disease, thereby generating new therapeutic strategies and molecular targets. We have focused on elucidating the mechanisms by which thrombin activates platelets and other cells. Thrombin's actions on platelets are thought to be critical for hemostasis and thrombosis, and its actions on leukocytes, endothelial, and mesenchymal cells may contribute to inflammatory and proliferative responses to vascular injury. The cloning and characterization of a thrombin receptor under HL44907 provided a major step forward in our understanding of thrombin signaling. The novel proteolytic mechanism of receptor activation revealed by these studies raised exciting new questions and provided fresh opportunities for the next project period: 1) What are the molecular interactions that specify receptor recognition and cleavage by thrombin and what is thrombin's precise role in receptor activation? 2) The thrombin receptor's novel proteolytic activation mechanism is irreversible. What are the mechanisms which terminate thrombin receptor signaling? 3) The irreversibly activated thrombin receptor exhibits a novel intracellular trafficking pattern that is very distinct from that of the well-studied and reversibly liganded beta 2- adrenergic receptor, even when both receptors are expressed in the same cell. What are the molecular signals which specify the thrombin receptor's novel intracellular trafficking pattern? By understanding the molecular machinery regulating thrombin receptor function we will generate new pharmacologic and genetic strategies for manipulating thrombin signaling. Lessons from this model system will no doubt apply to others. Potential health relevance includes fostering the development of new antithrombotic and antiproliferative therapies as well as the identification of new genetic risk factors for thrombosis and vascular disease.
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