Aortic Aneurysm Formation: Mechanisms of Oxidative Stress-Induced MMP Expression

点击翻译按钮获取中文摘要

The current proposal outlines a rigorous program of education and research to facilitate the applicant's development into an independent physician-scientist in the area of aneurysm pathobiology. The applicant, Dr. Matthew Eagleton, is a board-certified vascular surgeon at the Cleveland Clinic, with a principle interest in aortic aneurysms. Training will be performed by the Sponsor, Dr. Linda Graham. Her laboratory, in the Department of Biomedical Engineering of the Lerner Research Institute (LRI), has a major emphasis on the pathobiology of the blood vessel wall. Drs. Suneel Apte, Guy Chisolm, and George Stark, extablished investigators within the LRI, as well as Dr. Alan Daugherty from the University of Kentucky, will serve as an Advisory Committee during the course of this research. This proposal will investigate the mechanisms by which oxidative stress regulates matrix metalloproteinase (MMP) expression during aortic aneurysm formation. To achieve this goal, animal and cellular models will be used to address the following specific aims: 1) To determine the mechanisms by which reactive oxygen species (ROS) upregulate MMP production, specifically the role if protein kinase Cdelta in ROS-induced MMP-2, MMP-9, MT1-MMP, and tissue inhibitor of metalloproteinase (TIMP)-2 expression in aortic smooth muscle cells and macrophages; 2) Define the mechanisms by which activated PKC-isoenzymes regulate MMP expression, specifically addressing the roles of STAT1 and STATS, members of the JAK/STAT pathway; and 3) Determine the role of ROS in MMP regulation during experimental AAA formation in vivo. Relevance: Abdominal aortic aneurysms are a major health concern with a prevalance estimated between 1-9% of the general population. Currently, the only mode of treatment involves surgical repair of the aneurysm before it ruptures, a complication which often results in death. A better understanding of the pathogenesis of AAA formation could lead to the development of pharmacotherapies used to prevent aneurysm expansion and rupture.