PSMD6基因及其相关多态性位点rs831571对胰岛B细胞功能的影响及机制研究

项目名称： PSMD6基因及其相关多态性位点rs831571对胰岛B细胞功能的影响及机制研究

项目编号： No.81500610

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王天歌

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 科学防控2型糖尿病的当务之急在于探寻其致病机制和干预靶点。遗传因素参与的胰岛B细胞功能障碍是2型糖尿病的重要致病环节。全基因组关联研究发现PSMD6（rs831571）是东亚人群2型糖尿病的易感基因，其表达产物26S蛋白酶体调节亚基（PSMD6）是泛素-蛋白酶体系统的重要组分，可通过调控胰岛B细胞存活、胰岛素分泌及胰岛素信号通路影响胰岛B细胞功能。本研究前期发现中国汉族人群中PSMD6（rs831571）基因与2型糖尿病患病风险及胰岛B细胞功能受损密切相关。基于前期工作，本研究拟在临床层面、细胞及动物实验中，运用基因敲除、细胞转染、膜片钳及高胰岛素-正糖钳夹技术，从PSMD6基因表达、胰岛素生成、储存和分泌及胰岛B细胞增殖和凋亡方面探讨PSMD6（rs831571）基因影响胰岛B细胞功能的机制。该研究将为探索2型糖尿病预防和干预靶点贡献重要临床应用价值。

中文关键词： 2型糖尿病；胰岛B细胞功能障碍；PSMD6基因；26S蛋白酶体；高胰岛素-正糖钳夹试验

英文摘要： The prevalence of type 2 diabetes has increased significantly in recent decades and is now reaching epidemic proportions in China. Type 2 diabetes has become a major public health problem in the general population, and greatly handicapped the development of economy in China. It is imperative to identify the pathogenesis of type 2 diabetes and explore the potential targets for prevention and intervention. Genetics-involved pancreatic beta-cell dysfunction is a significant feature of type 2 diabetes. A recent GWAS has identified PSMD6 (rs831571) as a susceptibility loci for type 2 diabetes in East Asian populations. The expression product of PSMD6 that acts as a regulatory subunit of the 26S proteasome is involved in the ubiquitin-proteasome system, which regulates beta-cell survival, insulin secretion, and insulin signaling pathway. In our previous study, we found that PSMD6 (rs831571) variant was significantly associated with type 2 diabetes risk and beta-cell dysfunction in Chinese Han population. Based on our previous findings, we aimed to comprehensively study the effect of PSMD6 (rs831571) on beta-cell function and clarify the molecular mechanism of PSMD6 involved in the pathogenesis of type 2 diabetes. We designed to perform the studies in vitro (cell lines), in vivo (mice models) and in clinical levels, by using gene knockout, cell transfection, patch clamp and hyperinsulinemic-euglycemic clamp techniques. This study will provide valuable evidence to elucidate the molecular genetic mechanism for pathogenesis, and indicate potential targets for efficient intervention and prevention of type 2 diabetes.

英文关键词： Type 2 diabetes;Pancreatic beta-cell dysfunction;PSMD6 gene;26S proteasome;Hyperinsulinemic-euglycemic clamp