DsbA-L蛋白调控胰岛β细胞功能的机制研究

二硫键A氧化还原酶类似蛋白DsbA-L作为近期我们实验室新发现的分子伴侣蛋白已被证实在胰岛素靶器官（如肝脏、脂肪）对抵抗肥胖诱导的内质网和线粒体应激起重要保护作用。然而我们前期数据表明在人或小鼠胰岛中DsbA-L表达与年龄和肥胖呈正相关。我们发现胰岛β细胞特异性DsbA-L敲除小鼠葡萄糖耐量改善；反之，胰岛β细胞特异性过表达DsbA-L导致小鼠葡萄糖耐量减低。此外，在MIN6细胞过表达DsbA-L降低线粒体相关基因表达。这些结果表明，与在其它胰岛素靶器官中的保护功能截然相反，DsbA-L对胰岛β细胞功能起负调控作用。然而DsbA-L如何负调控胰岛β细胞全然不知。本项目将首次利用本实验室建立的胰岛β细胞特异性 DsbA-L基因敲除或过表达小鼠模型、β细胞模型及人胰岛模型，从在体、细胞和分子三个不同层面系统研究DsbA-L对胰岛β细胞功能调控，为预防β细胞功能衰竭，治疗糖尿病提供新靶点和思路。

Disulfide-bond A oxidoreductase-like protein (DsbA-L) is a chaperone-like protein that plays a key role in protecting obesity-induced endoplasmic reticulum (ER)- and mitochondrial-stress in insulin targeting tissues such as liver, fat and kidney. We have made an unexpected finding that DsbA-L expression is positively correlated with aged human and obese mice. In addition, ablation and overexpression of DsbA-L in pancreatic β cell alleviated and induced, respectively, high fat diet-induced glucose intolerance. Furthermore, overexpression of DsbA-L in MIN6 cells decreased mitochondrial-related gene expression. These results reveal that, unlike the protectively role of DsbA-L in other insulin target tissues, DsbA-L negatively regulates pancreatic β cell function. In this project, we will use pancreatic β cell-specific DsbA-L knockout and overexpression mouse and cell models, and human islets model to elucidate the mechanism by which DsbA-L regulates pancreatic β cell function. We believe that our study will provide important information on the regulation of pancreatic β cell function, which could reveal potential new strategies and new drug targets for the clinical treatment of diabetes.