老化肠上皮细胞ERS/UPR导致KIT蛋白减少和肠黏膜屏障受损的分子机制研究

肠黏膜屏障的退行性改变是老年人群易发肠道菌群失调和炎性肠病的主要原因。我们发现SCF/KIT信号通路在维持肠黏膜屏障结构与功能上起着关键作用，而老年人群和小鼠（24月龄）的肠上皮细胞表达KIT蛋白明显减少，但发生机制尚不清楚。肠黏膜老化常见明显的ROS堆积和ERS/UPR，被认为是导致KIT蛋白减少的直接因素。因此，本项目拟用2月、16月和24月龄小鼠，以模拟20岁、50岁和70岁的人类老化过程，利用高脂饮食和H2O2分别构建小鼠和细胞的氧化应激模型以及KIT功能丢失突变（wadsm/m）小鼠、ERS/UPR下游基因敲除小鼠，结合褪黑素/白藜芦醇等抗氧化剂干预方法，深入研究肠上皮老化ROS堆积-错误折叠/未成熟蛋白聚积-ERS/UPR所致KIT蛋白减少与黏膜屏障结构和功能受损的分子机制，为明确老年人群易罹患肠道菌群失调与炎性肠病的发生机制、探索有效延缓老化进程方法等提供新的思路和实验依据。

The degeneration of intestinal mucosa are the main risk factors for aging-associated bacterial dysbiosis and inflammatory bowel disease. Our previous study indicated that the SCF/KIT signaling plays a pivotal role in maintaining structure and function of intestinal mucosal barrier, and KIT protein expressed in intestinal epithelial cells displayed a decline in aged humans and mice. However, the underlying mechanism is still not fully clarified. Reactive oxygen species (ROS) accumulation and endoplasmic reticulum stress and unfolded protein response (ERS/UPR) , which are common in the aging intestinal mucosa, are considered the main cause of reduction in KIT. Therefore, in the present project, mice are divided into three groups according to age: 2-, 16-, and 24-month-old, to simulate life phases at about 20, 50, and 70 years of age in human. Furthermore, the cellular and animal models of high-fat diet/hydrogen peroxide-induced oxidative stress as well as the loss of function of c-kit mice (Wadsm/m), combined with antioxidant intervention including melatonin and resveratrol, and inhibition of downstream of ERS/UPR signaling, are applied for clarifying the mechanism of low expression of KIT and impairment of intestinal mucus barrier during aging, which caused by aging-induced oxidative stress and ERS/UPR, hoping this project will provide a new research perspective and theoretical basis for further study on bacterial dysbiosis and inflammatory bowel disease in the geriatric population.