MMP-2 Regulation in Aortic Aneurysm

描述（由申请人提供）： 腹主动脉瘤（AAA）是一种常见疾病，也是老年人死亡和发病的主要原因。肾下主动脉瘤的病因仍然不清楚，虽然增加蛋白水解似乎是这个过程的基础。我们以前已经确定了一个转录介导的增加总和加工/活性基质金属蛋白酶-2（MMP-2）在AAA组织。MMP-2是AAA所必需的，我们小组最近的实验工作表明MMP-2敲除小鼠对动脉瘤诱导具有抗性。我们目前令人兴奋的新的初步数据显示，MMP-2的mRNA和蛋白水平增加，在AAA患者的皮肤相比，动脉粥样硬化闭塞性疾病（AOD;动脉粥样硬化无动脉瘤）或控制（最小动脉粥样硬化，无动脉瘤）的患者。血浆MMP-2水平也增加了AAA相比，AOD或控制。这一最新发现表明MMP-2的全身性过度表达，与腹主动脉瘤患者在腹部手术后发生切口疝的已知倾向一致。在MMP-2启动子中发现的单核苷酸多态性中，只有一个通过破坏Sp-1结合位点来改变MMP-2蛋白水平。我们推测系统性MMP-2失调导致动脉瘤形成。该提案将通过以下方式研究MMP-2代谢的多个方面：1）确定AAA、AOD和对照患者的较大组的血液中的MMP-2蛋白水平; 2）确定AAA和AOD患者中MMP-2启动子中的常见功能性多态性的频率; 3）测定短干扰RNA分子（siRNA）在鼠AAA模型中抑制MMP-2表达和防止动脉瘤形成的能力; 4）确定巨噬细胞源性MT 1-MMP在MMP-2活化中的作用。目标1的目标是开发AAA的筛查测试。目的2可以确定一个重要的潜在机制，并解释个体对AAA的易感性。目标3中待测试的siRNA具有作为用于研究和治疗的特异性分子工具的巨大潜力。常驻MMP生产和局部激活的炎症细胞（具体目标4）之间的相互作用是一个重要的基础问题，在基质生物学。这个提议所解决的问题的答案将大大推进我们目前对AAA和其他与基质破坏相关的炎症性疾病过程的认识。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a common disease and a leading cause of death and morbidity in the elderly. The etiology of infrarenal aortic aneurysms remains obscure although increased proteolysis appears to be fundamental to this process. We have previously identified a transcriptionally-mediated increase in total and processed/active matrix metalloproteinase-2 (MMP-2) in AAA tissue. That MMP-2 is required for AAA has been established by recent experimental work from our group showing that MMP-2 knockout mice are resistant to aneurysm induction. We present exciting new preliminary data showing that MMP-2 mRNA and protein levels are increased in the skin of AAA patients in comparison to patients affected with atherosclerotic occlusive disease (AOD; atherosclerosis without aneurysms) or controls (minimal atherosclerosis, no aneurysm). Plasma MMP-2 levels are also increased in AAA compared to AOD or controls. This latest finding suggests systemic over-expression of MMP-2 and is consistent with the known propensity of AAA patients to get incisional hernias after abdominal surgery. Among the single nucleotide polymorphisms found in the MMP-2 promoter, only one alters MMP-2 protein levels by disrupting an Sp-1 binding site. We I hypothesize that systemic MMP-2 dysregulation leads to aneurysm formation. This proposal will investigate a number of aspects of MMP-2 metabolism by: 1) determining MMP-2 protein levels in the blood of a larger group of AAA, AOD and control patients; 2) determining the frequency of a common, functional polymorphism in the MMP-2 promoter in AAA and AOD patients; 3) determining the ability of short interfering RNA molecules (siRNA) to inhibit MMP-2 expression and prevent aneurysm formation in a murine AAA model; 4) determining the role of macrophage-derived MT1-MMP in the activation of MMP-2. The goal of aim 1 is to develop a screening test for AAA. Aim 2 could identify an important underlying mechanism and explain individual susceptibility to AAA. The siRNA to be tested in aim 3 has great potential as a specific molecular tool for investigation and therapy. The interaction between resident MMP production and local activation by inflammatory cells (specific aim 4) is an Important fundamental question in matrix biology. Answers to the questions addressed by this proposal will greatly advance our current knowledge of AAA and other inflammatory disease processes associated with matrix destruction.