This proposal defines a 5 year program of education and research designed to establish the independence of the principal investigator in a career as an academic vascular surgeon. The education component builds on vascular research training successfully completed as a resident at the Washington University School of Medicine. The research component of this program is designed to develop the practical skills necessary for a productive research career as well as establish independent success in a novel approach to the study of abdominal aortic aneurysms. Dr. Robert Thompson will provide coordinated mentorship and expertise in aneurysm pathology. The advisory committee is similarly comprised of very successful researchers and authorities including Dr. Stephen Schwartz who will provide support for the biology of vascular smooth muscle cells along with Dr. Robert Mecham who will support the studies in elastin metabolism. Dr. J. Perren Cobb's proficiency in performance and analysis of microarrarys will provide critical assistance with the expression studies. These studies will focus on the vascular smooth muscle cell (SMC) and its unique role in the characteristic pathologic changes of abdominal aortic aneurysms (AAA), particularly the loss of medial elastic fiber. Under normal conditions these cells are critical for the production and maintenance of the arterial wall extracellular matrix, and abnormal function of these cells is central to other aortic diseases such as atherosclerosis. Because we have observed unique characteristics and elastolytic activities of these cells in vitro and m vivo, we believe that these cells are phenotypically unique and that these changes support the development of an elastolysis characteristic of AAA. These investigations will compare aneurysm SMC to SMC from normal aorta and atherosclerotic plaque to i) determine if vascular SMC derived from human AAA tissues exhibit a unique differentiation phenotype compared to SMC derived from atherosclerotic plaque and normal aorta, 2) characterize the expression and regulation of elastolytic proteases and protease inhibitors by aneurysm cells compared to normal and atherosclerotic cells, and 3) determine whether aneurysm SMC are uniquely capable in mediating elastic fiber degeneration compared to non-aneurysmal vascular SMC. The abdominal aortic aneurysm is a silent, progressive and ultimately deadly weakening of the aortic wall that affects a large proportion of the elderly male population. Despite a long incubation period and easy means of detection, no pharmacologic therapy currently exists to prevent progression of small aortic aneurysms due to an incomplete understanding of the pathophysiology. The goal of these studies is to open the door for new therapeutics by developing an understanding of the role of the resident smooth muscle cell on this arterial wall failure.
