GENE TRANSFER IN MODELS OF ARTERIAL INJURY

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The broad objective of my research is to understand the molecular mechanisms of smooth muscle cell growth and to develop strategies to limit cell proliferation in arteries after injury based upon pathophysiology. The major limitations to therapeutic interventional procedures within peripheral or coronary arteries are thrombosis and intimal formation. We hypothesize that intimal cell growth and thrombosis are regulated by cell cycle proteins and prothrombotic proteins, respectively. Cytotoxic and cytostatic approaches may limit cell growth following vascular injury. In order to address these hypotheses, we propose three specific aims: (1) to optimize nonviral vectors to improve gene expression in vascular cells, (2) to examine the pathophysiology of smooth muscle cell growth in injured porcine and hyperlipidemic rabbit arteries and to develop cytotoxic approaches to limit intimal formation, and (3) to examine the role of thrombosis in intimal formation following vascular injury by investigating a factor X gene and a gene that encodes a factor Xa inhibitor.