Vascular occlusion, leading to attenuated flow in the microcirculation and tissue ischemia, is the proximate cause of angina, myocardial infarction, transplant vasculopathy, hypertension and stroke. The overall goal and integrating theme of our proposed Program of research is to develop effective gene therapy approaches for the treatment of vaso-occlusive disorders. The objectives of the Program deal with the outstanding issues that will need to be addressed before the potential benefits of gene th3rapy for this group of disorders can be fully realized. The objectives are as follows: 1. To develop strategies for accurate, efficient gene delivery to various relevant vascular structures. 2. To study the kinetic profiles of gene expression using different vectors and gen transfer strategies such that absolute level and durability of gene expression can be tailored to a given therapeutic approach. 3. To develop a generic strategy that can be used to monitor the expression of therapeutic transgenes in preclinical and clinical studies 4. To develop and optimize promising gene therapy approaches to the treatment of vaso-occlusive diseases. The program comprises four mutually reinforcing projects which, with core facility support, will collective address the objectives of the overall Program. Project 1 will employ a novel vascular stent seeded with genetically modified smooth muscle cells to deliver VEGF into the coronary circulation to induce angiogenesis in a porcine model of chronic total coronary occlusion. Project 2 will study adenoviral and lentiviral vectors for genetic modification of cardiac allotransplants and will go on to test the value of eNOS gene transfer for the control of post-transplant vasculopathy in rat and porcine models. Project 3 will use adenoviral vectors to transfer heme subarachnoid hemorrhage. Project 4 will develop a generally applicable strategy to monitor in vivo the expression of any vector encoded transgene. These synergistic studies are supported by an Administrative/Biostatistics Core and by a Vector Core support function that has been incorporated into Project 4. Together, the project leaders, collaborators, co-directors and members of the Internal Advisory Board have formed a highly interactive, collegial group with the collective knowledge, experience, motivation, and ability to address the state objectives in the context of this Program Project Grant.
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