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

主动脉瘤形成：氧化应激诱导 MMP 表达的机制

• 批准号: 8113407
• 负责人: Matthew Jeremiah Eagleton
• 金额: $ 12.91万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113407
• 关键词: Abdominal Aortic Aneurysm; Address; Advisory Committees; Aneurysm; Angiotensin II; Animal Model; Antioxidants; Aortic Aneurysm; Area; Bacteriophages; Biomedical Engineering; Blood Vessels; Cardiovascular Diseases; Cell model; Cessation of life; Clinic; Complication; Data; Development; Education; Enzymes; Extracellular Matrix; Fibroblasts; Gelatinase A; Gelatinase B; General Population; Goals; Health; Homeostasis; Human; Hyperlipidemia; Interstitial Collagenase; Investigation; Isoenzymes; Janus kinase; Kentucky; Laboratories; Lead; Matrix Metalloproteinases; Metalloproteases; Modeling; Mus; Operative Surgical Procedures; Oxidases; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmacotherapy; Physicians; Play; Process; Production; Protein Kinase; Protein Kinase C; Proteins; Reactive Oxygen Species; Regulation; Research; Research Institute; Research Personnel; Role; Rupture; STAT protein; STAT1 gene; Scientist; Smoking; Smooth Muscle Myocytes; Structural Protein; Surgeon; Testing; Tissue Inhibitor of Metalloproteinases; Tissues; Training; Universities; Up-Regulation; base; human MMP14 protein; in vivo; inhibitor/antagonist; interest; macrophage; member; mouse model; prevent; programs; repaired; response; shear stress

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.

目前的提案概述了一个严格的教育和研究计划，以促进申请人的 发展成为动脉瘤病理生物学领域的独立医生-科学家。申请人， 博士马修·皮特尔顿是克利夫兰诊所的一名董事会认证的血管外科医生， 主动脉瘤培训将由申办者琳达格雷厄姆博士进行。她的实验室， 勒纳研究所（LRI）生物医学工程系，主要侧重于 血管壁的病理生物学苏尼尔·阿普特、盖伊·奇索姆和乔治·斯塔克博士 LRI内部的调查人员，以及来自肯塔基州大学的艾伦·道金斯博士，将担任 咨询委员会在研究过程中。 本研究将探讨氧化应激调控基质的机制 基质金属蛋白酶（MMP）表达在主动脉瘤形成。为了实现这一目标，动物和 细胞模型将用于解决以下具体目标：1）确定机制， 活性氧（ROS）上调MMP的产生，特别是蛋白激酶C δ的作用， 在ROS诱导MMP-2、MMP-9、MT 1-MMP和金属蛋白酶组织抑制剂（TIMP）-2中 在主动脉平滑肌细胞和巨噬细胞中的表达; 2）定义激活的机制， PKC同工酶调节MMP表达，特别是STAT 1和STATS的作用， JAK/STAT途径的成员;和3）确定ROS在MMP调节过程中的作用。 体内实验性AAA形成。 相关性： 腹主动脉瘤是一个主要的健康问题，估计发病率在1-9%之间。 普通民众。目前，唯一的治疗模式包括动脉瘤的手术修复， 它会破裂，这是一种并发症，通常会导致死亡。更好地了解AAA的发病机制 形成可能导致用于防止动脉瘤扩张的药物疗法的发展， 破裂