TRB3参与脂毒性诱导胰岛β细胞凋亡的机制研究

项目名称： TRB3参与脂毒性诱导胰岛β细胞凋亡的机制研究

项目编号： No.81200616

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： 彭亮

作者单位： 中日友好医院

项目金额： 23万元

中文摘要： 脂毒性导致的胰岛β细胞功能衰竭是2型糖尿病发病的一个重要环节，但相关分子机制还不十分清楚。本课题组前期通过建立体外和体内模型模拟胰岛β细胞在高游离脂肪酸情况下的凋亡，然后通过基因芯片差异筛选和体外基因沉默实验首次发现TRB3参与了脂毒性诱导的胰岛β细胞凋亡。本研究拟应用Wistar大鼠和自发性糖尿病GK大鼠，检测高脂饲料喂养条件下糖尿病不同阶段胰岛β细胞TRB3表达的差异，分析其与血脂浓度和β细胞凋亡的关系；应用稳定敲降TRB3的胰岛β细胞系和已建立的可诱导表达TRB3的胰岛β细胞系，在体内和体外分析TRB3的基因沉默或高表达对脂毒性诱导β细胞凋亡的影响，阐明TRB3介导脂毒性诱导β细胞凋亡的分子机制，为研究2型糖尿病胰岛β细胞功能衰竭的发病机制提供新的实验证据和潜在的干预靶点。

中文关键词： 糖尿病；胰岛β细胞；凋亡；脂毒性；TRB3

英文摘要： Lipotoxicity-induced pancreatic β cell dysfunction is a critical component in the pathogenesis of type 2 diabetes, but the underlying molecular mechanisms remain to be elucidated. In our previous work, we established in vitro and in vivo models to mimic the pancreatic β cell apoptosis under high free fatty acid condition. Genes that related to lipotoxicity-induced β cell apoptosis were screened by microarray, and the candidate gene TRB3 was first confirmed to have an important role in lipotoxicity-induced β cell apoptosis by in vitro siRNA experiment. This study aims to detect TRB3 expression of pancreatic β cells in Wistar rats and spontaneously diabetic GK rats at different stage of diabetes, and then analysis its relation with serum lipids and pancreatic β cells apoptosis; We also want to investigate the role of TRB3 in lipotoxicity-induced apoptosis by using TRB3 stable knockdown INS-1 cells and our established TRB3 inducible INS-1 cells in vitro and in vivo, and elucidate its molecular mechanism. We hope this study can provide some valuable experimental evidence and therapeutic target for preventing and treating pancreatic β cell apoptosis in type 2 diabetes.

英文关键词： diabetes；pancreatic beta cell；apoptosis；lipotoxicity；TRB3