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

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.

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。

本课题从2型糖尿病易感基因PSMD6（rs831571）对胰岛beta细胞功能和血糖代谢的影响为切入点，系统分析糖尿病易感基因、环境因素、基因-环境交互作用对2型糖尿病和相关代谢异常的综合影响，为探索2型糖尿病预防和干预靶点提供重要临床科学依据。本课题在大规模人群队列水平，基于一系列包括PSMD6（rs831571）在内的2型糖尿病易感位点建立了2型糖尿病遗传风险评分，深入探讨了包括PSMD6（rs831571）在内的多个糖尿病易感位点以及糖尿病遗传风险评分对胰岛beta细胞功能与2型糖尿病的影响，同时进一步研究了糖尿病易感位点和遗传风险评分与环境内分泌干扰物、体重、饮食等主要环境因素在2型糖尿病及肥胖发病风险中的交互作用，创新性提示2型糖尿病和肥胖精准预防的干预靶点，取得了系列成果。该系列研究对2型糖尿病等代谢性疾病的病理机制探讨及精准预防和治疗具有重要科学价值和社会意义，研究成果在2型糖尿病等代谢性疾病的功能学研究、分子流行病学及临床疾病风险分层和预测方面有很好的应用前景。