Flow responses to carotid angioplasty

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DESCRIPTION (provided by applicant): This proposal is a five-year training program for the development of Alan Dardik's academic career in Vascular Surgery. Dr. Dardik completed surgical training at the Johns Hopkins Hospital and is currently Assistant Professor of Surgery at Yale University School of Medicine. This training program will allow him to develop, coordinate, and translate laboratory findings into practical clinical applications for the diagnosis and treatment of patients with atherosclerotic carotid disease, and allow him to develop into an independent investigator including preparation and submission of an R-01 proposal. William Sessa, PhD, Professor of Pharmacology and Director of the Vascular Cell Signaling and Therapeutics Program, and Co-Director of the Yale/NHLBI Proteomics Center, and Bauer Sumpio, MD, PhD, Professor of Surgery at Yale, will serve as comentors, and guide Dr. Dardik's research and career development, including instruction in the Responsible Conduct of Research. Dr. Dardik will closely interact with senior faculty in Yale's Interdepartmental Vascular Biology and Transplant Program such as Jordan S Pober, MD, PhD. Stroke affects 2% of Americans, with an annual incidence of 700,000 strokes, and cost of over $50 billion; women and minorities are disproportionally affected. Carotid angioplasty (CA) is a rapidly evolving endovascular treatment for carotid stenosis, preventing stroke. However, the hemodynamic responses following CA are not well defined and may influence the outcome and long-term durability of CA. The applicant hypothesizes that plaque fracture and endothelial denudation after CA directly expose smooth muscle cells (SMC) to complicated arterial flow; complicated flow directly stimulates SMC Akt activity, leading to SMC proliferation, suppression of apoptosis, and ultimately vessel restenosis. This proposal will examine the response to CA in an animal model, including development of a novel surgical model of complicated flow, development of MRI techniques to assess flow velocity distribution and wall shear stress, and examination of the role of Akt using knockout mice. The response of SMC directly to laminar and complicated flow in vitro will be examined with molecular biological techniques. The specific aims are: 1. Determine the effects of carotid angioplasty on flow in vivo. 2. Determine the effects of carotid angioplasty on Akt and mTOR pathway activation. 3. Compare the effects of simple and complicated flow on SMC proliferation and apoptosis. The information obtained in this proposal will provide a framework to rationally examine and direct therapy for our patients. The academic environment, diverse resources, and enthusiasm for research at Yale will maximize the potential for Dr Dardik to establish an academic career as a clinician scientist. This proposal seeks to understand the complex mechanisms by which vascular intervention such as angioplasty or bypass surgery fail prematurely. By developing techniques to detect abnormal flow patterns and understanding the effects of these flow patterns on smooth muscle cells, we hope to develop vascular interventions that are longer-lasting and minimize patient suffering. (End of Abstract)