application) Gene transfer technology is under intense evaluation for gene therapy, but its real promise may be as a tool for investigating the molecular and cellular mechanisms of vascular disease. Gene transfer using adenoviral vectors has been successful in treating neointimal proliferation following vascular balloon injury, but the vector itself induces substantial inflammation and cellular proliferation. Fortunately, second generation adenoviral vectors have substantially reduced viral replication and structural gene expression, and therefore, may represent nearly inert gene transfer vectors. Accordingly, the PI will study the effect of these newer vectors on vascular gene transfer, determining their effect on acute and chronic inflammation and their ability to effect long-term vascular transgene expression. Subsequently, he will use this vector to investigate the origin and subsequent effects of endothelial dysfunction that is present in the earliest phases of the atherogenic process in cholesterol-fed rabbits. Specifically, he will determine whether adenoviral transfer of genes designed to enhance vascular nitric oxide or reduce superoxide will favorably affect the atherosclerotic process. The proposed studies will establish the degree to which second-generation adenoviral vectors improve upon first-generation vectors, and will define the extent of problems that remain. In addition, the proposed studies will use adenoviral gene transfer as a tool to enhance understanding of the early phases of atherosclerosis. The achievement of these goals will contribute to our understanding of atherosclerosis atherogenesis, and increase the likelihood that vascular gene therapy will prove to be an effective option for treatment of human atherosclerosis.
