转位相关蛋白alpha（TRAPα）在胰岛素生物合成和beta细胞功能及糖稳态中的作用

从胞浆向ER的跨膜转位是所有分泌蛋白进入分泌通路的第一个关键步骤，位于ER膜上的转位相关蛋白α(TRAPα)可选择性地促进新合成分泌蛋白的跨膜转位，其基因多态性与T2DM易感性密切相关。我们前期研究证实敲除β细胞系中TRAPα，可降低前胰岛素原跨膜转位效率，并影响胰岛素原从ER向高尔基体的前向转运，导致成熟胰岛素合成减少，但其确切机制仍有待明确。本课题将在明确TRAPα对前胰岛素原跨膜转位方式和效率，以及其对胰岛素原前向转运的作用和分子机制基础上，应用我们刚建立的β细胞特异性TRAPα基因敲除小鼠，动态观察TRAPα对小鼠糖代谢、β细胞胰岛素合成和分泌、细胞凋亡、分化增殖的影响，揭示TRAPα对维持机体血糖稳态作用及其机制。本研究将不仅加深我们对TRAPα作用分子机制的理解，同时还有助于揭示与TRAPα功能缺陷相关的β细胞功能衰竭和糖尿病的病理生理学基础，以期为靶向治疗糖尿病提供新思路。

Transmembrane translocation from cytoplasm to ER is the first key step for all secreted proteins to enter the secretory pathway. Translocon-associated protein subunit α（TRAP α）on ER membrane can selectively promote transmembrane translocation of newly synthesized secreted proteins, and its gene polymorphism is closely related to T2DM susceptibility. Our previous study confirmed that knockout of TRAP α in the β cell line can not only reduce the transmembrane translocation efficiency of preproinsulin, but also affect the proinsulin trafficking from ER to Golgi, resulting in reduced synthesis of mature insulin, but the exact mechanism remains to be clarified. This project will observe the effect of TRAP α on glucose metabolism in TRAP α beta cell-knockout mice specific, the synthesis and secretion of insulin, the apoptosis, differentiation and proliferation of β cell on the basis of exploring the exact molecular mechanism of TRAP α affecting transmembrane translocation mode and efficiency of preproinsulin, and the proinsulin trafficking to Golgi, in order to reveal the mechanism of TRAP α maintaining the body's glucose steady balance . This study will not only deepen our understanding of the molecular mechanism of TRAP α physiology effect，but also help to reveal the pathophysiological basis of β cell dysfunction and diabetes related to TRAP α defect, so as to provide new ideas for targeted treatment of diabetes mellitus.