内质网是分泌蛋白和膜蛋白折叠成熟的主要场所，具有适合二硫键形成的氧化还原环境。氧化还原稳态是内质网发挥功能最重要的特性之一，其失衡会引起内质网应激及其功能紊乱，将广泛影响细胞生命活动，导致糖尿病、神经退行性疾病和癌症等疾病。但内质网氧化还原稳态调节的分子机制特别是有关还原力来源至今尚不清楚。本项目申请拟在不同层面研究细胞如何维持健康的内质网氧化还原稳态：（1）内质网定位的氧化还原酶(蛋白质二硫键异构酶家族成员、Ero1、Prx4等)和胞质定位的硫氧还蛋白及其还原酶在调节内质网氧化还原稳态中的不同贡献；（2）鉴定参与胞质内质网间跨膜电子传递的分子；（3）内质网氧化还原失衡引起蛋白质质量控制系统的变化及其对分泌蛋白和膜蛋白生物合成的效应。以上研究将阐明内质网氧化还原稳态的调控机制，有助于揭示与内质网功能紊乱密切相关疾病的分子机理，也为未来通过调节内质网氧化还原稳态人工干预这一类疾病提供新思路。

The endoplasmic reticulum (ER) is the compartment responsible for synthesis and folding of secretory and membrane proteins, with a tightly controlled redox homeostasis necessary for disulfide bond formation. Disruption of the ER redox homeostasis will cause ER stress and dysfunction, which is linked to the pathogenesis of many diseases including diabetes, neurodegenerative disorders, and cancer. However, the molecular mechanism of the ER redox homeostasis regulation and its source of reducing equivalents are still largely unknown. This project aims to study how cells maintain a health ER redox homeostasis in different aspects. We will address the roles of the oxidoreductases located in the ER lumen including protein disulfide isomerases, Ero1 and Prx4, as well as the cytosolic thioredoxin - thioredoxin reductase pathway, in regulating the ER redox homeostasis. We will identify the unknown molecule(s) responsible for transmembrane electron transfer between the ER and cytosol. We will also trace the consequent changes of the protein quality control system and the fate of secretory and membrane proteins after the disruption of the ER redox homeostasis. Our studies will provide a better understanding of the regulation of the ER redox homeostasis, and its relation with ER stress related diseases.