MOLECULAR MECHANISMS OF ANEURYSMAL DEGENERATION

动脉瘤变性的分子机制

• 批准号: 6527093
• 负责人: Robert W. Thompson
• 金额: $ 30.8万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527093
• 关键词: aorta aneurysm; cellular pathology; collagenase; elastases; enzyme inhibitors; gene expression; genetic regulation; genetically modified animals; immunocytochemistry; laboratory mouse; light microscopy; molecular pathology; nuclear runoff assay; pathologic process; phagocytes; phorbols; plasmin; plasminogen activator; protein degradation; stromelysin; tetracyclines; tissue /cell culture; tissue inhibitor of metalloproteinases; urokinase; western blottings

DESCRIPTION (Adapted from Applicant's Abstract): Abdominal aortic aneurysms (AAAs) are a common degenerative disease with life-threatening implications. The purpose of this research program is to better understand the regulation of individual gene products within the aneurysmal aorta and their parthophysiologic implications in disease progression. A novel murine model of elastase-induced aortic injury has been developed that recapitulates many critical features of human AAA, including transmural infiltration of the aortic wall by mononuclear phagocytes, increased local production of matrix metalloproteinases (MMPs), and progressive degradation of aortic wall collagen and elastin. Using this model, it has been shown that mice with targeted gene disruption of MMP-9 exhibit a significant reduction in aneurysmal degeneration. It has also been shown that the treatment with doxycycline reduces aortic wall expression of MMP-9 in patients undergoing elective AAA repair, and that doxycycline suppresses phorbol-stimulated expression of MMP-9 in cultured human THP-1 mononuclear phagocytes. These studies suggest that inflammatory cell production of MMP-9 plays a critical role in the process of aneurysmal degeneration and that treatment with doxycycline has the potential to repress mononuclear phagocyte expression of this enzyme. This project will extend these observations by identifying the critical molecular steps involved in elastase-induced aneurysmal degeneration in the mouse and by elucidating the molecular pathways by which aneurysmal degeneration might be suppressed by MMP-inhibiting tetracyclines. These goals will be accomplished through four specific aims: (1) determine if the generation of biologically-active elastin degradation peptides is responsible for leukocyte recruitment, aortic wall infiltration, and MMP expression during the initiation of elastase-induced AAA; (2) clarify the molecular mechanisms(s) by which targeted deletion of MMP-9 suppresses the development of elastase-induced AAA; (3) establish if urokinase-type plasminogen activator (u-PA) or additional MMPs are required in the development of elastase-induced AAA; and (4) define the molecular mechanism(s) by which doxycycline suppresses PMA-stimulated expression in cultured human THP-1 mononuclear phagocytes, and determine if a reduction in MMP-9 expression can explain the protective effects of doxycycline in vivo. These investigations can be expected to add considerably to our understanding of the molecular mechanisms of aneurysmal degeneration, potentially forming the basis for new treatment strategies.

描述（改编自申请人的摘要）：腹主动脉瘤 （AAA）是一种常见的退行性疾病，具有危及生命的影响。 该研究计划的目的是更好地了解监管 动脉瘤主动脉内的个体基因产物及其 疾病进展中的部分生理学影响。一种新型小鼠模型 弹性蛋白酶诱导的主动脉损伤已被开发出来，概括了许多 人类 AAA 的关键特征，包括主动脉的透壁浸润 通过单核吞噬细胞破坏壁，增加局部基质的产生 金属蛋白酶 (MMP) 和主动脉壁胶原蛋白的逐渐降解 和弹性蛋白。使用这个模型，已经表明带有目标基因的小鼠 MMP-9 的破坏表现出动脉瘤变性的显着减少。 还表明，强力霉素治疗可减少主动脉壁 接受选择性 AAA 修复术的患者中 MMP-9 的表达 强力霉素抑制培养人中佛波醇刺激的 MMP-9 表达 THP-1 单核吞噬细胞。这些研究表明炎症细胞 MMP-9的产生在动脉瘤形成过程中起着至关重要的作用 变性，用多西环素治疗有可能抑制 单核吞噬细胞表达这种酶。该项目将扩展这些 通过识别参与的关键分子步骤进行观察 弹性蛋白酶诱导的小鼠动脉瘤变性并通过阐明 抑制动脉瘤变性的分子途径 MMP 抑制四环素。这些目标将通过四个方面来实现 具体目标：（1）确定是否产生具有生物活性的弹性蛋白 降解肽负责白细胞募集、主动脉壁 弹性蛋白酶诱导的 AAA 启动过程中的浸润和 MMP 表达； (2)阐明MMP-9靶向缺失的分子机制 抑制弹性蛋白酶诱导的 AAA 的发展； (3) 建立如果 需要尿激酶型纤溶酶原激活剂 (u-PA) 或其他 MMP 弹性蛋白酶诱导的 AAA 的发展； (4) 定义分子 多西环素抑制 PMA 刺激表达的机制 培养人 THP-1 单核吞噬细胞，并确定是否减少 MMP-9的表达可以解释多西环素的体内保护作用。 这些调查预计将大大增加我们的理解 动脉瘤变性的分子机制，可能形成 新的治疗策略的基础。