蛋白酶体激活促进腹主动脉瘤发生的分子机制研究

项目名称： 蛋白酶体激活促进腹主动脉瘤发生的分子机制研究

项目编号： No.81470586

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 郑月宏

作者单位： 中国医学科学院北京协和医院

项目金额： 72万元

中文摘要： 炎症反应和血管平滑肌细胞（VSMC）表型转换是调节腹主动脉瘤（AAA）发生主要机制。泛素-蛋白酶体系统（UPS）在调节T淋巴细胞介导的炎症和VSMC表型转换中发挥重要作用。我们前期研究表明T淋巴细胞参与AAA的发生，同时发现人及AopE-/-小鼠AAA组织中蛋白酶体亚基β5、β5i表达水平均明显增高，应用蛋白酶体抑制剂Bortezomib处理可显著抑制AopE-/-小鼠AAA的发生。然而β5、β5i参与AAA发生的分子机制仍不清楚。因此，申请人拟应用特异性抑制剂及基因敲除动物，进行体内、体外实验，采用免疫染色、Western blot、qPCR 等方法，观察β5、β5i对AAA发生率、病变程度、炎症反应等指标的影响，明确β5、β5i调节炎症、VSMC表型转换及AAA发生的分子机制。本项目将阐明蛋白酶体激活介导AAA的发生的分子机制，为寻找新的药物靶点提供理论依据。

中文关键词： 腹主动脉瘤；蛋白酶体；血管平滑肌细胞；炎症反应；分子机制

英文摘要： Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aging men. Among the numerous pathophysiologic mechanisms, inflammation, vascular smooth muscle cell (VSMC) phenotypic modulation play pivotal role. 26S proteasome, the central proteolytic unit of the the ubiquitin-proteasome system (UPS), plays a critic role in the regulation of the mechanisms mentioned above. β5 is one of three functional constitutive subunits of proteasome, mediating the chymotrypsin-like activity. By the action of the intended proinflammatory cytokines, the β5 subunits can be transferred into β5i, composing the immunoproteasome and mediating the enhanced chymotrypsin-like activity. And β5i plays important role in inflammatory response and autoimmune diseases. Recently, we have discovered the enhancement of β5 and β5i function in human and mice AAA tissues. Proteasome inhibitor Bortezomib could attenuate development of AAAs in Ang II-induced ApoE-/- mice, especially by suppressing β5 and β5i function. But the underlying mechanisms of proteasome activation on AAA formation have not been well defined. And how β5 and β5i respectively regulate VSMC phenotypic modulation and inflammation, and the correspondence patterns of the two mechanisms still remain unknown. On the basis of preliminary experiments, the project intends to solve the problems and shed light on the underlying interaction of inflammation response and VSMC phenotypic modulation in AAA formation. All experiments will be performed at the level of animal model and cell culture, and the specific role of β5i will be tested by specific inhibitor or gene knockout. We will use immunohistochemistry, qPCR, Western blot analysis, et al, to investigate the precise molecular mechanisms. In this way, we aim to find a potential target for future strategies designed to monitor and combat AAAs.

英文关键词： abdominal aortic aneurysm;proteasome;myocytes;smooth muscle;inflammation;molecular mechanism