Molecular Mechanisms of Aneurysmal Degeneration

动脉瘤变性的分子机制

• 批准号: 6973707
• 负责人: Robert W. Thompson
• 金额: $ 34.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6973707
• 关键词: aorta aneurysm; bone marrow transplantation; cellular pathology; collagen; collagenase; cysteine endopeptidases; elastases; elastin; flow cytometry; gene deletion mutation; genetically modified animals; laboratory mouse; light microscopy; molecular pathology; tissue inhibitor of metalloproteinases

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAAs) are a common and life-threatening condition. The goal of this project is to elucidate cellular and molecular mechanisms responsible for aortic wall degeneration using a mouse model of elastase-induced AAAs previously characterized in our laboratory. This model recapitulates many critical features of human AAAs, including transmural infiltration of the aortic wall by rnononuclear phagocytes, increased local production of proinflammatory cytokines and matrix metalloproteinases (MMPs). and progressive degradation of elastin and collagen. We have shown that targeted deletion of MMP-9 inhibits elastase-induced AAAs with suppression of elastin degradation, whereas AAAs are enhanced in the absence of the endogenous MMP inhibitor, TIMP-1. Because we found even greater enhancement of AAAs in mice lacking both MMP-9 and TIMP-1, more detailed knowledge is needed regarding the in vivo interactions between MMP-9, TIMP-1, and other elastolytic MMPs, and the specific role of MMP-9 in aortic elastin degradation. It is also important to consider if altered susceptibility to AAAs will occur in mice with resistance to collagenase-mediated degradation of interstitial collagen or in mice lacking expression of coilagenase-3 (MMP-13), one of the principal MMP-collagenases. Because we have observed suppression of elastase-induced AAAs in mice with targeted deletion of cathepsin-S (Cst-S), an elastolytic and collagenolytic cysteine protease, the mechanisms by which Cat-S promotes aneurysmal degeneration also need to be defined. These issues will be addressed by accomplishing the following three specific aims: (1) Clarify how MMP-9, TIMP-1 and other elastolytic MMPs influence the development of eiastase-induced AAAs, if MMP-9 is directly responsible for aortic wall elastin degradation in vivo, and if matrilysin (MMP-7) is required for aneurysmal degeneration; (2) Establish if MMP-mediated degradation of interstitial (type I) collagen is required in the development of experimental AAAs and if MMP-13 is essential in this process; and (3) Identify the functionally important cellular sources of Cat-S during the development of elastaseinduced AAAs and the molecular mechanisms by which targeted gene deletion of Cat-S suppresses aneurysmal degeneration. Taken together, these studies will contribute important new information on the mechanisms underlying extracellular matrix degradation in aneurysmal degeneration.

描述（由申请人提供）： 腹主动脉瘤（AAA）是一种常见且危及生命的疾病。本项目的目的是阐明细胞和分子机制，负责主动脉壁变性使用弹性蛋白酶诱导的AAAs小鼠模型先前在我们的实验室的特点。该模型概括了人AAA的许多关键特征，包括单核巨噬细胞对主动脉壁的透壁浸润，促炎细胞因子和基质金属蛋白酶（MMP）的局部产生增加。以及弹性蛋白和胶原蛋白的逐渐降解。我们已经表明，有针对性地删除MMP-9抑制弹性蛋白酶诱导的AAAs与抑制弹性蛋白降解，而AAAs增强的内源性MMP抑制剂，TIMP-1的情况下。因为我们发现在缺乏MMP-9和TIMP-1的小鼠中AAA的增强更大，所以需要关于MMP-9，TIMP-1和其他弹性蛋白溶解MMP之间的体内相互作用以及MMP-9在主动脉弹性蛋白降解中的特定作用的更详细的知识。同样重要的是要考虑是否会改变对AAA的敏感性将发生在对胶原酶介导的间质胶原降解具有抗性的小鼠中或在缺乏胶原酶-3（MMP-13）（主要MMP-胶原酶之一）表达的小鼠中。因为我们已经观察到在靶向缺失组织蛋白酶-S（Cst-S）（一种弹性蛋白溶解和胶原溶解半胱氨酸蛋白酶）的小鼠中抑制弹性蛋白酶诱导的AAA，所以还需要确定Cat-S促进囊性变性的机制。（1）阐明MMP-9、TIMP-1和其他弹性蛋白溶解性MMP如何影响弹性蛋白酶诱导的AAA的发展，MMP-9是否直接负责体内主动脉壁弹性蛋白降解，以及基质溶解素（MMP-7）是否是血管平滑肌变性所必需的;（2）确定MMP介导的间质（I型）胶原的降解是否在实验性AAA的发展中是必需的，以及MMP-13是否在该过程中是必需的;（3）确定Cat-S在弹性蛋白酶诱导的AAAs形成过程中的重要功能细胞来源以及Cat-S靶向基因缺失抑制AAAs变性的分子机制。总之，这些研究将有助于重要的细胞外基质降解的机制，在垂体退行性变的新信息。