This proposal describes a 5 year training program for the development of an academic career in Vascular Surgery. The principal investigator has completed a residency program in General Surgery at The University of Chicago, a two year research fellowship in Vascular Biology at The University of Chicago and a Vascular Surgery Fellowship at the University of Pennsylvania. The PI will now expand upon his scientific skills through a unique integration of interdepartmental resources at The University of Chicago. This program will promote the command of vascular biology, physiology and gene therapy as applied to neointimal hyperplasia, a leading cause of bypass graft and vascular stent failure. Ralph Weichselbaum, M.D. will mentor the principal investigators scientific development. Dr. Weichselbaum is the Daniel K. Ludwig Professor and Chair of the Department of Radiation and Cellular Oncology at The University of Chicago and is a recognized leader in gene therapy, DMA recombination and repair signal transduction as well as angiogenic therapy. To augment the training, the program will enlist an advisory board of experts including Bernard Roizman, Sc.D., Professor, Molecular Genetics and Cell Biology, Biochemistry and Molecular Biology as well as Lewis Schwartz, M.D., Divisional Vice President Abbott Vascular and former Associate Professor of Surgery at The University of Chicago, Hisham Bassiouny, Professor and Interim section Chief of Vascular Surgery, and Jeffrey Mathews, the Dallas B. Phemister Professor and Chairman of the Department of Surgery. Research will focus on the prevention of neointimal hyperplasia (NH) of vascular smooth muscle cells (VSMC). Recent work by me, while in the laboratory of Lewis Schwartz, demonstrated that a mutant strand of Herpes Simplex Virus-1 (HSV-1) in an in vivo rabbit model system, infects all vascular layers without prior injury to the endothelium;expresses a reporter gene driven by a viral promoter with high efficiency for at least 4 weeks;exhibits no systemic toxicity;can be eliminated at will by administration of the antiviral drug acyclovir;and significantly reduces VSMC proliferation and restenosis in vein grafts. The proposed experiments will use surgical, histological, biochemical and cellular techniques to elucidate the mechanism by which the HSV-1 prevents NH.
The specific aims of the study are 1) To test the hypothesis that a brief exposure of vascular tissue to genetically-engineered Herpes simplex-1 virus (HSV-1) will attenuate NH;2) To test the hypothesis that a brief exposure of vascular tissue to the HSV-1 mutant is safe;3) To test the hypothesis that HSV infection is a factor that alters the orderly sequence of programmed cellular events and has been shown to be cell type specific.
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