MOLECULAR MECHANISMS OF ANEURYSMAL DEGENERATION

描述：(改编自研究人员摘要)腹主动脉 动脉瘤(AAA)是一种日益重要的血管疾病，由 弹性介质的结构退化。调控因素 弹性纤维在不同阶段的降解和修复 疾病过程尚不清楚。慢性炎症和产量增加 弹性分解基质金属蛋白酶(MMPs)的特征是 已建立的AAA，特别是92-kD明胶酶的表达 动脉瘤-浸润性巨噬细胞。反映人类疾病，92-KD 明胶酶在实验性AAA大鼠模型中升高， 复制在人类AAA中看到的组织重塑事件。这样做的目的是 提案是为了阐明细胞和分子机制 AAA的发展、渐进性扩张和破裂 弹力酶诱导的大鼠AAA是由 弹性降解基质金属蛋白酶的表达及其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 单核巨噬细胞明胶酶在实验各时相的变化 动脉瘤样变性，这种基质金属蛋白酶在体内是如何调节的，以及 阻断其药理作用的后果。我们还将检查 弹性蛋白纤维修复在对抗血管紧张素转换酶损伤中的作用 蛋白水解性弹性蛋白降解。最后，我们将确定 高血压与腹主动脉扩张性增高的关系 弹性降解基质金属蛋白酶及其参与连接蛋白的表达 组织修复。确定导致疾病发生的分子机制 动脉瘤变性将促进新的治疗方法的发展 针对这一常见疾病过程的战略。

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.