肠道ZnT8调控GLP-1参与2型糖尿病及代谢调节的机制研究

锌转运蛋白8（ZnT8）是基因组学发现的与2型糖尿病（T2DM）显著相关的蛋白，但是其与T2DM发病的关系及机制仍未完全阐明。前期实验中，我们首次发现ZnT8在肠道内分泌细胞中表达，全身敲除ZnT8可以影响肠道激素水平、肠道内环境以及肠道菌群。本项目中，我们拟通过ZnT8肠道及肠道L细胞特异性敲除小鼠，结合体外小鼠L细胞系STC-1细胞，利用多种分子生物学及动物生理学检测手段，明确肠道ZnT8对全身代谢及肠道稳态的影响，深入研究其对肠道L细胞的增殖凋亡、GLP-1的合成分泌的作用及分子机制。ZnT8是极有前景的糖尿病治疗靶点，明确ZnT8在不同组织及不同生理病理状态下的生物学功能，将为开发ZnT8活性调节剂治疗糖尿病提供重要的生物学基础。

Zinc transporter 8 (ZnT8) is closely associated with type 2 diabetes mellitus (T2DM). However the mechanism by which ZnT8 contributes to T2DM pathogenesis is still elusive. Our previous study demonstrated that ZnT8 was expressed in enteroendocrine cells, regulating the enteroendocrine hormone level, intestinal enviroment and microbiota. In this project, we aimed to investigate the specific role of intestinal ZnT8 in systemic and intestinal homeostasis, especially GLP-1 producing L cells, by using tissue-specific ZnT8 knockout mice and murine L cell line STC-1 cell. ZnT8 is a very promising drug target for T2DM. Our study will clarify the novel function of ZnT8 in intestinal tract under different physiological context, which provides an important biological basis for developing ZnT8 activity modulator against T2DM.