E3泛素连接酶Synoviolin对胰岛β细胞功能的影响

项目名称： E3泛素连接酶Synoviolin对胰岛β细胞功能的影响

项目编号： No.81200558

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 陈芳

作者单位： 南京医科大学

项目金额： 23万元

中文摘要： 研究表明，E3泛素连接酶所致的胰岛β细胞功能障碍在2型糖尿病的发病中发挥重要作用。本课题前期研究结果显示，脂肪酸可显著上调β细胞内E3泛素连接酶Synoviolin的表达和FoxO1的转录活性。进一步研究发现，干扰Synoviolin显著逆转脂肪酸引起的MafA表达降低，同时免疫共沉淀的结果提示Synoviolin与MafA之间存在直接相互作用。由此，我们推测，E3泛素连接酶Synoviolin可能参与了β细胞的脂毒性。本研究的目的，就是借助于各种胰岛β细胞功能研究的方法和分子生物学技术，从FoxO1介导的Synoviolin转录调控以及Synoviolin介导的MafA降解机制入手，系统阐述Synoviolin对胰岛β细胞功能的影响及其作用机制。本项目意义在于揭示E3泛素连接酶Synoviolin与2型糖尿病β细胞功能障碍之间的内在联系，有助于深入探讨2型糖尿病的发病机制。

中文关键词： Synoviolin；2型糖尿病；胰岛β细胞；MafA；脂毒性

英文摘要： A lot of scientific research indicated that pancreatic β-cells dysfunction induced by E3 ubiquitin ligases play a critical role in the pathogenesis of type 2 diabetes. Our preliminary results showed that fatty acid significantly stimulated the E3 ubiquitin ligase Synoviolin expression and enhanced FoxO1 transcriptional activity in pancreatic β-cells. Further studies showed that silencing of Synoviolin expression significantly reversed the expression of MafA inhibited by fatty acid. Besides, the result from co-immunoprecipitation showed that Synoviolin could interact?with?MafA. As a result, we speculated that the E3 ubiquitin ligase Synoviolin may be involved in β-cells lipotoxicity. To investigate the mechanism of FoxO1 regulating Synoviolin transcription as well as Synoviolin degradating MafA protein, we will use various methods of the study on pancreatic β-cell function and perform a variety of molecular biology techniques. Then, we will systematically explain the mechanism of Synoviolin involved in pancreatic β-cell dysfunction. Therefore, the significance of this project is to reveal the intrinsic link between the E3 ubiquitin ligase Synoviolin and the dysfunction of pancreatic β-cells, which is helpful to explore in depth the pathogenesis of type 2 diabetes.

英文关键词： Synoviolin；type 2 diabetes；Pancreatic β-cells；MafA；lipotoxicity