线粒体蛋白SIRT5对氧化/硝化应激诱导胰岛beta细胞损伤的调控作用及机制研究

项目名称： 线粒体蛋白SIRT5对氧化/硝化应激诱导胰岛beta细胞损伤的调控作用及机制研究

项目编号： No.81202574

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 刘率男

作者单位： 中国医学科学院药物研究所

项目金额： 23万元

中文摘要： 沉默信息调节因子SIRT5是线粒体内的一种NAD+依赖的蛋白去乙酰化酶。它的作用底物之一是线粒体诱导细胞凋亡过程中的重要因子细胞色素C，但其确切的调控机制仍未阐明。目前，对线粒体蛋白SIRT5在胰岛beta细胞中的作用和调节机制国内外尚无报道。前期研究中，我们发现SIRT5在正常和糖尿病小鼠的胰腺中均有表达且存在显著差异，其表达水平与几种线粒体凋亡关键因子的变化呈现一定相关性。因此，我们推测："线粒体蛋白SIRT5可能参与调控氧化/硝化应激诱导的beta细胞损伤"。为证实该假说，本项目拟采用过表达、基因沉默和免疫共沉淀等技术方法，从整体和细胞多个层面，考察SIRT5在beta细胞损伤及凋亡进程中的重要生理功能并探讨其作用机制。本研究将揭示SIRT5与beta细胞功能受损的关系及调控方式，从新的视角阐明beta细胞损伤的分子机制，并为寻找药物作用新靶点和拓展糖尿病治疗新思路奠定实验基础。

中文关键词： SIRT5；细胞凋亡；beta细胞；Bcl-XL；胰岛素分泌

英文摘要： Silent information regulators- - Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD+)-depended deacetylases. In mammals, seven genes have been identified as SIRT 1-7. SIRT5, primarily localized in the mitochondrial matrix, regulating the metabolic enzymes activity and oxidative stress pathway. Cytochorme C (Cyto C) as one of the SIRT5 substrates, is a conserved mitochondrial intermembrane space protein, and has a central function in oxidative metabolism as well as apoptosis initiation. SIRT5 exhibited deacetylase activity against acetylated Cyto C, suggesting a role of regulating stress-induced mitochondrial-dependent apoptosis. In the last five years, some evidences had indicated that SIRT5 played an important role in controlling the development of atherosclerosis, alcoholic steatohepatitis and age-related disease. However few studies have examined the direct association between the biological function of mitochondrial SIRT5 and diabetes. Our previous studies found that SIRT5 was also expressed in the mice pancreatic tissue, and the expression level of SIRT5 is variant in pancreas between the normal and diabetic mice.Therfore, we hypothesized that mitochondrial SIRT5 may play a critical role during the pancreatic beta cell apoptosis induced by elevated ROS/RNS in diabetes. To elucidate wh

英文关键词： SIRT5；cell apoptosis；beta cell；Bcl-XL；insulin secretion