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: 7901528
• 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/7901528
• 关键词: Abdominal Aortic Aneurysm; Address; Advisory Committees; Aneurysm; Angiotensin II; Animal Model; Animals; 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; Membrane; Metalloproteases; Modeling; Mus; Operative Surgical Procedures; Oxidative Stress; Oxis; 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; Specific qualifier value; 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; rosin; 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项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内科科学家。申请人， 马修·伊格尔顿博士是克利夫兰诊所获得董事会认证的血管外科医生，主要感兴趣的是 在主动脉瘤中。培训将由赞助商琳达·格雷厄姆博士进行。她的实验室，在 勒纳研究所(LRI)生物医学工程系的主要重点是 血管壁的病理生物学。Suneel Apte博士、Guy Chsolm博士和George Stark博士 LRI的调查人员以及肯塔基大学的艾伦·多尔蒂博士将担任 在这项研究的过程中，我是咨询委员会的成员。 这项建议将研究氧化应激调节基质的机制。 金属蛋白酶在主动脉瘤形成过程中的表达。为了实现这一目标，动物和 将使用细胞模型来解决以下具体目标：1)通过以下方式确定机制 哪些活性氧物种(ROS)上调基质金属蛋白酶的产生，特别是在蛋白激酶C增量的作用 在ROS诱导的基质金属蛋白酶-2、基质金属蛋白酶-9、基质金属蛋白酶1-基质金属蛋白酶和金属蛋白酶组织抑制因子-2 在主动脉平滑肌细胞和巨噬细胞中的表达；2)确定激活的机制 PKC同工酶调节基质金属蛋白酶的表达，特别涉及STAT1和STATS的作用， JAK/STAT通路的成员；以及3)确定ROS在基质金属蛋白酶调节中的作用。 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，发病率估计在1%-9%之间。 普通民众。目前，唯一的治疗方式是对之前的动脉瘤进行手术修复 它破裂，这是一种并发症，通常会导致死亡。对腹主动脉瘤发病机制的进一步认识 形成可能导致药物疗法的发展，用于防止动脉瘤扩大和 破裂。