Prostacyclin (PGI2), a derivative of arachidonic acid, plays an important role promoting vascular smooth muscle relaxation and preventing platelet aggregation. The actions are mediated through a poorly understood seven transmembrane domain spanning G-protein coupled receptor (GPCR), the prostacyclin receptor (IP). The clinical importance of this receptor stems from its involvement in cardiovascular diseases such as myocardial infarction, stroke, atherosclerosis, and hypertension. The potential use of prostacyclin in the treatment of pulmonary hypertension, and cancers (colon, breast and lung), is currently being intensely investigated. We have recently discovered eleven human prostacyclin receptor polymorphisms. Furthermore preliminary in vitro studies have revealed abnormal function in one of these polymorphisms (R212H). This has led to the hypothesis that such polymorphisms may play a critical role in cardiovascular disease. Through three Specific Aims the goal of this proposal is to understand the pharmacogenetic importance of hIP polymorphisms and in so doing to determine distinct features of this receptor, which enable it to bind a 20-carbon fatty acid (eicosanoid) and couple it to signal transduction pathways, leading to cardiovascular disease. Genomic screening and sequencing will be used to comprehensively search for new polymorphisms and assess association with clinical cardiovascular disease (Specific Aim #1). Novel polymorphisms found will be tested in vitro using site-directed mutagenesis, and structure-function studies (Specific Aim #2).
Specific Aim #3 will focus on downstream signal transduction pathways in human vascular smooth muscle cells to determine mechanisms for cardiovascular defects. In addition to this proposed collaboration between the Pharmacology, Medicine (Statistics), Vascular Surgery, Cardiology and Pathology Departments here at Dartmouth, strong groups in protein structure-function and signal transduction, will be critical resources for addressing these Specific Aims. Achievement of these aims, should not only improve our understanding of the molecular genetics and structure-function of the prostacyclin receptor, but may also provide the critical biochemical understanding to explain interindividual differences in progress of cardiovascular disease and variable responses associated with prostacyclin analogue treatment.
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