Gene transfer of adenylyl cyclase to pulmonary smooth muscle cells

这一假说被认为是腺酰环化酶(CA)异构体的基因转移可以用来增加肺动脉平滑肌细胞(PASMC)环磷酸腺苷(CAMP)的合成和作用。PASMC的功能在与肺动脉高压相关的各种重要临床条件下会发生变化，它将与腺病毒或其他病毒载体一起用于评估AC 6和8型的基因转移，这两种AC亚型具有独特的调节模式。我们将评估AC表达增加对cAMP生成和“下游”反应的影响，包括激活cAMP依赖的蛋白激酶、代谢、收缩和生长反应，以及对离子通道活性和表达的影响。其他研究将评估来自原发性肺动脉高压患者的PASMC细胞AC表达和功能的区隔。综上所述，这些研究将为AC向PASMC的基因转移以及AC表达增加对PASMC功能的影响提供新的信息。这些研究的成功完成将为启动PASMC功能异常患者的临床研究提供实验基础。

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.