ANEURYSM RESEARCH CORE COLLABORATIVE R01

动脉瘤研究核心协作 R01

• 批准号: 6390632
• 负责人: Robert W. Thompson
• 金额: $ 7.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390632
• 关键词: aorta aneurysm; biomedical facility; cell bank /registry; cell line; cooperative study; histopathology; human tissue; laboratory mouse; laboratory rat

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 NIMP-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.

腹主动脉瘤（AAA）是一种常见的退化性疾病，具有威胁生命的影响。 尽管AAA发展的基础的病理生理事件仍然很少了解，但它们显然涉及主动脉壁结缔组织的退化重塑。 最近的研究暗示了这种重塑的病理学模式的三个过程：（1）纤维外细胞外基质蛋白的修复受损，（2）慢性单核炎症，以及（3）基质降解蛋白酶的局部过量产生。 该协作研究计划的目的是更好地了解调节这三个过程的分子机制。 首先，博士。威廉·帕克斯（William C. Parks）和迈克尔·希普利（J. Michael Shipley）将检查似乎限制动脉瘤壁环境中有效产生弹性纤维的分子因素。 使用从人类和实验性AAA获得的组织以及培养中源自动脉瘤的血管平滑肌细胞，他们将专门评估控制型托磷脂基因表达和tropoelastin mRNA稳定性的分子途径，以及涉及弹性纤维组装的其他基因产物的调节，例如Fiber fiber组装，例如Fibrillin-1和Latents Trent-latents Trent-latents Trentta-tanga。 其次，杰伊·海尼克（Jay Heinecke）博士将研究与慢性炎症相关的蛋白质氧化，这是组织破坏的重要途径。 使用新型方法来检测和测量不同氧化途径对蛋白质修饰的贡献，他将确定人和实验AAA中的主要氧化途径，阐明蛋白质氧化如何用于促进基质金属蛋白酶在动脉瘤组织中的基质金属酶活性，并检查遗传操纵如何改变特定氧化途径的遗传性可能会影响特定的氧化途径。 第三，罗伯特·W·汤普森（Robert W. Thompson）博士将研究来自疾病的各个阶段的人AAA组织的三种不同间隙胶原酶的调节表达，以及暴露于促炎细胞因子，凤梨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（MMP-13），从而为血管壁细胞中NIMP-13表达的调节提供了新的见解。通过这三个紧密联系的研究获得的知识将有助于促进我们对主动脉瘤分子病理生理学的理解，这可能会导致新的治疗策略。