REGULATED EXPRESSION OF COLLAGENASES IN AAA

腹主动脉瘤(AAA)是一种常见的具有生命危险的退行性疾病。虽然AAA发生的病理生理事件仍不清楚，但它们明显涉及到主动脉壁结缔组织的退行性重塑。最近的研究表明，在这种重塑的病理模式中有三个过程：(1)纤维细胞外基质蛋白的修复受损，(2)慢性单核炎症，(3)局部过度产生基质降解蛋白。这个合作研究项目的目的是更好地了解调节这三个过程的分子机制。首先，威廉·C·帕克斯博士和J·迈克尔·希普利博士将研究似乎限制动脉瘤壁环境中弹性纤维有效产生的分子因素。利用从人和实验性AAA和动脉瘤来源的血管平滑肌细胞培养中获得的组织，他们将专门评估控制原弹性蛋白基因表达和原弹性蛋白mRNA稳定性的分子途径，以及参与弹性纤维组装的其他基因产物的调节，如纤维蛋白-1和潜在的转化生长因子-β结合蛋白-2。其次，Jay Heinecke博士将研究与慢性炎症相关的蛋白质氧化，作为组织破坏的重要途径。他将使用新的方法检测和测量不同氧化途径对蛋白质修饰的贡献，确定人类和实验性AAA中的主要氧化途径，阐明蛋白质氧化如何促进动脉瘤组织中的基质金属蛋白酶活性，并研究影响特定氧化途径的基因操作如何改变小鼠模型的动脉瘤发展。第三，罗伯特·W·汤普森博士将研究三种不同间质胶原酶的调节表达，这三种间质胶原酶既存在于疾病不同阶段的人类AAA组织中，也存在于暴露于促炎细胞因子、佛波酯和强力霉素的培养的SMC中。这些研究将特别关注胶原酶-3(MMP13)，为调节MMP13在血管壁细胞中的表达提供新的见解。通过这三项密切相关的研究所获得的知识将有助于我们加深对主动脉瘤分子病理生理学的理解，有可能导致新的治疗策略。

Abdominal aortic aneurysms (AAAs) are a common degenerative disease with life-threatening implications. While the pathophysiologic events underlying the development of AAA are still poorly understood, they clearly involve degenerative remodeling of aortic wall connective tissue. Recent studies have implicated three processes in this pathologic pattern of remodeling: (1) impaired repair of fibrillar extracellular matrix proteins, (2) chronic mononuclear inflammation, and (3) excessive local production of matrix-degrading proteinases. The purpose of this collaborative research program is to gain better understanding of the molecular mechanisms regulating these three processes. First, Drs. William C. Parks and J. Michael Shipley will examine the molecular factors that appear to limit the effective production of elastic fibers in the aneurysm wall environment. Using tissues obtained from human and experimental AAA and aneurysm-derived vascular smooth muscle cells in culture, they will specifically evaluate the molecular pathways controlling tropoelastin gene expression and tropoelastin mRNA stability, as well as the regulation of additional gene products involved in elastic fiber assembly, such as fibrillin-1 and latent TGF-beta binding protein-2. Second, Dr. Jay Heinecke will examine protein oxidation associated with chronic inflammation as an important pathway of tissue destruction. Using novel methods to detect and measure the contributions of different oxidative pathways to protein modification, he will determine the dominant oxidative pathways in human and experimental AAA, elucidate how protein oxidation serves to promote matrix metalloproteinase activity in aneurysm tissue, and examine how genetic manipulation affecting specific oxidative pathways might alter aneurysm development in a mouse model. Third, Dr. Robert W. Thompson will examine the regulated expression of three different interstitial collagenases, both in human AAA tissues from various stages of disease and in cultured SMC exposed to proinflammatory cytokines, phorbol ester and doxycycline. These studies will have a particular focus on collagenase-3 (MMP-13), providing new insight into the regulation of MMP-13 expression in vascular wall cells. Knowledge gained through these three closely-linked studies will help advance our understanding of the molecular pathophysiology of aortic aneurysms, potentially leading to new treatment strategies.