信号肽序列受体1(SSR1)调节胰岛素前体进出内质网的作用及其分子机制

前胰岛素原跨内质网膜转位进入内质网和胰岛素原从内质网向高尔基体的前向转运，是胰岛β细胞合成成熟胰岛素的关键环节。最新研究表明，多种基因和环境因素可通过影响上述胰岛素前体进出内质网的效率，导致胰岛素合成的减少和糖尿病的发生，但具体机制有待阐明。我们的前期研究证实，2型糖尿病相关基因编码的SSR1在β细胞系的胰岛素合成中至关重要，但是SSR1对胰岛素合成影响的分子机制及其对机体血糖稳态的作用尚不明确。本项目利用β细胞特异性敲除SSR1小鼠，在明确SSR1调节胰岛素生物合成早期通路的分子机制的同时，阐明SSR1在正常生理和增龄情况下，维持β细胞功能和机体血糖稳态中作用，并进一步探究其在机体能量过负荷条件下，对β细胞代偿功能的影响及其病理生理学基础。本研究将加深对SSR1作用机制的理解，明确其在病理和生理条件下对β细胞功能维持和机体血糖稳态的作用，揭示其功能不足所致糖尿病的分子机制。

Insulin precursors translocation across endoplasmic reticulum membrane into lumen and subsequently transporting to Golgi are the critical steps of insulin maturation in pancreatic β cells. Recent studies have shown that many genetic and environmental factors can affect the efficiency of insulin precursors translocation in and out of the endoplasmic reticulum, leading to the reduction of insulin biosynthesis and the occurrence of diabetes. We have recently reported that SSR1, a type 2 diabetes-associated gene, is required for insulin biosynthesis in β cell lines. However, the pathophysiological significance of SSR1 in maintaining normal β cells function and glucose homeostasis remains unknown. By establishing a pancreatic β cell specific SSR1 knockout (SSR1 βKO) mouse line, in this study, we aim to elucidate the role of SSR1 in maintaining β cell function and glucose homeostasis under normal physiology and aging conditions, and further explore its effect on compensatory function and pathophysiological basis of β cells under metabolic stress. These results will provide the first in vivo evidence that ablation of SSR1 leads to defects in insulin production and glucose intolerance. This study will not only reveal pathophysiological significance of SSR1 in maintaining β cell function, but also provide insight into pathogenesis of type 2 diabetes associated with impaired SSR1 function.