MOLECULAR MECHANISMS OF ANEURYSMAL DEGENERATION

动脉瘤变性的分子机制

• 批准号: 2460215
• 负责人: Robert W. Thompson
• 金额: $ 13.35万
• 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 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460215
• 关键词: aorta aneurysm; cellular pathology; collagenase; cyclins; elastases; elastin; endopeptidases; enzyme linked immunosorbent assay; fibrillin; gene expression; hypertension; immunocytochemistry; immunoprecipitation; laboratory rat; macrophage; molecular pathology; polymerase chain reaction; protein degradation; radioimmunoassay; stromelysin; tissue inhibitor of metalloproteinases; western blottings

DESCRIPTION: (Adapted from investigator's abstract) Abdominal aortic aneurysms (AAA) are an increasingly important vascular disorder caused by structural degeneration of the elastic media. The factors regulating degradation and repair of elastic fibers during various phases of this disease process are unknown. Chronic inflammation and increased production of elastolytic matrix metalloproteinases (MMP's) are characteristic of established AAA, and in particular, the expression of 92-kD gelatinase by aneurysm-infiltrating macrophages. Reflecting the human disease, 92-kD gelatinase is increased in an experimental rat model of AAA which, as well, reproduces tissue remodeling events seen in human AAA. The purpose of this proposal is to elucidate the cellular and molecular mechanisms underlying the development, progressive expansion, and rupture of AAA by testing the hypothesis that elastase-induced AAA in the rat are caused by increased expression of elastolytic MMPs and that MMP-mediated elastin degradation exceeds connective tissue repair. We will focus on the expression of 92-kD gelatinase by mononuclear phagocytes during each phase of experimental aneurysmal degeneration, how this MMP is regulated in vivo, and the consequences of blocking its action pharmacologically. We will also examine the role played by elastin fiber repair towards counteracting the effects of proteolytic elastin degradation. Finally, we will determine the relationship between hypertension and increased expansion of AAA vis a vis the expression of elastolytic MMPs and proteins involved in connective tissue repair. Ascertaining the molecular mechanisms responsible for aneurysmal degeneration will facilitate the development of novel therapeutic strategies for this common disease process.

描述：（改编自研究者的摘要）腹主动脉 动脉瘤 (AAA) 是一种日益重要的血管疾病，其原因是 弹性介质的结构退化。 调节因素 在此过程的各个阶段中弹性纤维的降解和修复 发病过程不明。 慢性炎症和产量增加 弹力基质金属蛋白酶 (MMP) 的特征是 建立了 AAA，特别是 92-kD 明胶酶的表达 动脉瘤浸润巨噬细胞。 反映人类疾病，92-kD 在 AAA 实验性大鼠模型中，明胶酶增加，同时， 再现人类 AAA 中观察到的组织重塑事件。 这样做的目的 提议是阐明潜在的细胞和分子机制 通过测试 AAA 的发展、逐步扩展和破裂 假设大鼠中弹性蛋白酶诱导的 AAA 是由增加的 弹力分解基质金属蛋白酶 (MMP) 的表达以及 MMP 介导的弹性蛋白降解 超过结缔组织修复。 我们将重点关注 92-kD 的表达 实验各阶段单核吞噬细胞的明胶酶 动脉瘤样变性，这种 MMP 在体内是如何调节的，以及 从药理上阻断其作用的后果。 我们还将检查 弹性蛋白纤维修复在抵消以下影响方面发挥的作用 蛋白水解弹性蛋白降解。 最后，我们将确定 高血压与 AAA 扩张增加之间的关系 弹力基质金属蛋白酶和参与结缔组织的蛋白质的表达 组织修复。 确定负责的分子机制 动脉瘤变性将促进新型治疗方法的开发 针对这种常见疾病过程的策略。