A Novel Approach To Antiplatelet Therapy: Targeting ProteaseActivated Receptor 4
|Institution:||Case Western Reserve University|
|Full text PDF:||http://rave.ohiolink.edu/etdc/view?acc_num=case1440530967|
Protease activated receptors (PARs) are seven transmembrane G-protein coupled receptors that are activated by cleavage of their N-terminus by a protease. Upon cleavage of their N-terminus, the new N-terminus acts as a tethered ligand for the receptor. The ligand then binds to the corresponding receptor activating it. In the case of human platelets, which express PAR1 and PAR4, PAR cleavage by thrombin leads to signaling through Gq and G12/13 which causes numerous downstream intracellular effects in platelet activation including shape change, intracellular calcium release, secretion, and aggregation. To date the majority of PAR studies on platelets have focused on PAR1; however, PAR1 and PAR4 have distinct and overlapping signaling functions and affect the activation of one another. To more clearly understand the roles of PAR4 and to better understand the interplay between the two receptors, three main studies were conducted. First, heterodimerization of PAR1 and PAR4 was examined in detail. Secondly, studies were performed to evaluate the viability of targeting the anionic cluster on the N-terminus of PAR4 as an antiplatelet therapy target. Finally, PAR4 monoclonal antibodies were developed which are able to detect PAR4 expression and activation on human platelets. Advisors/Committee Members: von Lintig , Johannes (Committee Chair), Nieman, Marvin (Advisor).