REGULATED EXPRESSION OF COLLAGENASES IN AAA

AAA 中胶原酶的调控表达

• 批准号: 6184786
• 负责人: Robert W. Thompson
• 金额: $ 22万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184786
• 关键词: abdomen; aorta aneurysm; collagen; collagenase; cooperative study; cytokine; enzyme induction /repression; extracellular matrix; fibroblasts; genetic transcription; human tissue; isozymes; metalloendopeptidases; molecular pathology; phorbols; protein degradation; protein localization; tetracyclines; tissue /cell culture; vascular smooth muscle

Abdominal aortic aneurysms (AAAs) are a common degenerative disease with life-threatening implications. While the pathophysiologic events underlying the development of AAA are still poorly understood, they clearly involve degenerative remodeling of aortic wall connective tissue. Recent studies have implicated three processes in this pathologic pattern of remodeling: (1) impaired repair of fibrillar extracellular matrix proteins, (2) chronic mononuclear inflammation, and (3) excessive local production of matrix-degrading proteinases. The purpose of this collaborative research program is to gain better understanding of the molecular mechanisms regulating these three processes. First, Drs. William C. Parks and J. Michael Shipley will examine the molecular factors that appear to limit the effective production of elastic fibers in the aneurysm wall environment. Using tissues obtained from human and experimental AAA and aneurysm-derived vascular smooth muscle cells in culture, they will specifically evaluate the molecular pathways controlling tropoelastin gene expression and tropoelastin mRNA stability, as well as the regulation of additional gene products involved in elastic fiber assembly, such as fibrillin-1 and latent TGF-beta binding protein-2. Second, Dr. Jay Heinecke will examine protein oxidation associated with chronic inflammation as an important pathway of tissue destruction. Using novel methods to detect and measure the contributions of different oxidative pathways to protein modification, he will determine the dominant oxidative pathways in human and experimental AAA, elucidate how protein oxidation serves to promote matrix metalloproteinase activity in aneurysm tissue, and examine how genetic manipulation affecting specific oxidative pathways might alter aneurysm development in a mouse model. Third, Dr. Robert W. Thompson will examine the regulated expression of three different interstitial collagenases, both in human AAA tissues from various stages of disease and in cultured SMC exposed to proinflammatory cytokines, phorbol ester and doxycycline. These studies will have a particular focus on collagenase-3 (MMP-13), providing new insight into the regulation of MMP-13 expression in vascular wall cells. Knowledge gained through these three closely-linked studies will help advance our understanding of the molecular pathophysiology of aortic aneurysms, potentially leading to new treatment strategies.

腹主动脉瘤（AAA）是一种常见的退行性疾病，可危及生命。 虽然 AAA 发展的病理生理学事件仍然知之甚少，但它们显然涉及主动脉壁结缔组织的退行性重塑。 最近的研究表明这种病理重塑模式涉及三个过程：（1）纤维状细胞外基质蛋白的修复受损，（2）慢性单核炎症，以及（3）基质降解蛋白酶的局部过量产生。 该合作研究计划的目的是更好地了解调节这三个过程的分子机制。 首先，博士。 William C. Parks 和 J. Michael Shipley 将研究限制动脉瘤壁环境中弹性纤维有效产生的分子因素。 利用从人类和实验性 AAA 获得的组织以及培养的动脉瘤来源的血管平滑肌细胞，他们将专门评估控制弹性蛋白原基因表达和弹性蛋白原 mRNA 稳定性的分子途径，以及参与弹性纤维组装的其他基因产物的调节，例如原纤维蛋白-1 和潜在的 TGF-β 结合蛋白-2。 其次，Jay Heinecke 博士将研究与慢性炎症相关的蛋白质氧化作为组织破坏的重要途径。 他将使用新方法检测和测量不同氧化途径对蛋白质修饰的贡献，确定人类和实验性 AAA 中的主要氧化途径，阐明蛋白质氧化如何促进动脉瘤组织中的基质金属蛋白酶活性，并研究基因操作如何影响动脉瘤组织。特定的氧化途径可能会改变小鼠模型中动脉瘤的发展。 第三，Robert W. Thompson 博士将检查三种不同间质胶原酶的调节表达，包括不同疾病阶段的人类 AAA 组织和暴露于促炎细胞因子、佛波酯和多西环素的培养 SMC 中。 这些研究将特别关注胶原酶 3 (MMP-13)，为血管壁细胞中 MMP-13 表达的调节提供新的见解。通过这三项密切相关的研究获得的知识将有助于增进我们对主动脉瘤分子病理生理学的理解，并有可能带来新的治疗策略。