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.
|McCormick, Susan; He, Qi; Stern, Jordan et al. (2015) Evidence for the Use of Multiple Mechanisms by Herpes Simplex Virus-1 R7020 to Inhibit Intimal Hyperplasia. PLoS One 10:e0130264|
|Mak, Grace Z; Speaker, Christopher; Anderson, Kristen et al. (2013) Median arcuate ligament syndrome in the pediatric population. J Pediatr Surg 48:2261-70|
|Qato, Khalil; Harriman, David; Cao, Dingcai et al. (2013) Contemporary outcomes in vascular patients who require preoperative coronary stent. Ann Vasc Surg 27:646-54|
|Bryan, Darren S; Carson, John; Hall, Heather et al. (2013) Natural history of carotid artery occlusion. Ann Vasc Surg 27:186-93|
|Skelly, C L; He, Q; Spiguel, L et al. (2013) Modulating vascular intimal hyperplasia using HSV-1 mutant requires activated MEK. Gene Ther 20:215-24|
|Funaki, Brian; Birouti, Nour; Zangan, Steven M et al. (2012) Evaluation and treatment of suspected type II endoleaks in patients with enlarging abdominal aortic aneurysms. J Vasc Interv Radiol 23:866-72; quiz 872|
|Wu, Timothy; Carson, John G; Skelly, Christopher L (2010) Use of internal endoconduits as an adjunct to endovascular aneurysm repair in the setting of challenging aortoiliac anatomy. Ann Vasc Surg 24:114.e7-114.e11|
|Spiguel, Lisa R P; Chandiwal, Amito; Vosicky, James E et al. (2010) Concomitant proliferation and caspase-3 mediated apoptosis in response to low shear stress and balloon injury. J Surg Res 161:146-55|
|Loor, Gabriel; Skelly, Christopher L; Wahlgren, Carl-Magnus et al. (2009) Is atherectomy the best first-line therapy for limb salvage in patients with critical limb ischemia? Vasc Endovascular Surg 43:542-50|