PHARMACOLOGICAL REGULATION OF THE PROSTACYCLIN RECEPTOR

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Prostacyclin (PGI2) is a platelet inhibitory, vasodilator eicosanoid elaborated by vascular tissue in response to thrombotic and vasoconstrictor stimuli. This project aims to utilize this biological profile to address the hypothesis that overexpression of receptors for such homeostatic ligands might modulate the response to vascular occlusive events in vivo. Initially, this project aims to characterize the molecular events attendant to PGI2 receptor (IP2R) desensitization, using purification of an epitope tagged receptor, peptide-based antibodies and tandem mass spectrometry to direct the construction of desensitization resistant mutants. Wild type and mutant receptors will be delivered in adenoviral constructs to vascular cells and their effectiveness in limiting platelet-vessel wall interactions will be explored. These experiments will utilize in vitro systems and will lead to the use of in vivo models including an established canine model of thrombosis and an embryonic stem cell Ip2R receptor knock out mouse. The comparative efficacy of the wild type and mutant receptors will be assessed.