Gene transfer of adenylyl cyclase to pulmonary smooth muscle cells

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The overriding of this hypothesis is that gene transfer of isoforms of adenylyl cyclase (CA) can be used to increase cyclic AMP (cAMP) synthesis and action in pulmonary artery smooth muscle cells (PASMC). PASMC, whose function is altered in a variety of important clinical conditions associated with pulmonary arterial hypertension, will be used with adenoviral or other viral vectors to assess gene transfer of AC type 6 and 8, two AC isoforms with unique patterns of regulation. We will assess impact o increased AC expression on cAMP generation and on "downstream" responses including activation of cAMP-dependent protein kinase, metabolic, contractile and growth responses, and on ion channel activity and expression. Other studies will assess compartmentation of AC expression and function of PASMC cells derived from patients with primary pulmonary hypertension. Taken together, the proposed studies should provide new information regarding gene transfer of AC to PASMC and impact of increased AC expression of PASMC function. Successful completion of these studies would provide an experimental basis to initiate clinical studies in patients with abnormal PASMC function.