MOLECULAR MECHANISMS OF ANEURYSMAL DEGENERATION

描述(摘自申请者摘要)：腹主动脉瘤 (AAAS)是一种常见的退行性疾病，具有危及生命的影响。 这个研究项目的目的是为了更好地了解 动脉瘤样主动脉内的单个基因产物及其表达 疾病进展中的孤雌生理学意义。一种新的小鼠模型 弹性蛋白酶诱导的主动脉损伤已发展为许多 人腹主动脉瘤的关键特征，包括主动脉跨壁渗透 通过单核巨噬细胞壁，增加局部基质的产生 金属蛋白酶(MMPs)与主动脉壁胶原的进行性降解 还有弹性蛋白。利用这个模型，已经证明了携带靶向基因的小鼠 阻断基质金属蛋白酶-9可以显著减少动脉瘤的退变。 也有研究表明，多西环素的治疗可以减少主动脉壁。 基质金属蛋白酶-9在择期腹主动脉瘤修补术患者中的表达 多西环素抑制佛波醇刺激培养的人基质金属蛋白酶-9的表达 THP-1单核巨噬细胞。这些研究表明，炎性细胞 基质金属蛋白酶-9的产生在动脉瘤形成过程中起关键作用 退化和用多西环素治疗有可能抑制 单核巨噬细胞表达这种酶。该项目将扩展这些功能 通过确定涉及到的关键分子步骤进行观察 弹性蛋白酶诱导的小鼠动脉瘤样变性及通过阐明 抑制动脉瘤样变性的分子途径 抑制基质金属蛋白酶的四环素。这些目标将通过四个阶段实现 具体目标：(1)确定是否产生具有生物活性的弹性蛋白 降解肽负责白细胞的募集，主动脉壁 在弹性酶诱导的AAA形成过程中，细胞的浸润和基质金属蛋白酶的表达； (2)阐明基质金属蛋白酶-9靶向缺失的分子机制(S) 抑制弹性蛋白酶诱导的AAA的发展；(3)建立 需要尿激酶型纤溶酶原激活物(u-PA)或额外的MMPs 弹性酶诱导的AAA的发展；以及(4)定义分子 多西环素抑制PMA刺激的血管内皮细胞表达的机制(S) 培养的人THP-1单核巨噬细胞，并确定是否减少 基质金属蛋白酶-9的表达可以解释多西环素的体内保护作用。 这些调查可望大大增加我们的了解 动脉瘤样变性的分子机制，潜在地形成 为新的治疗策略奠定了基础。

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.