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

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

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