甘草泻心汤抑制内质网应激PERK-elF2α-CHOP信号通路保护UC肠黏膜屏障稳态的机制研究

Ulcerative colitis (UC) is a common disease of the digestive system whose treatment is difficult. Study has found that the destruction of intestinal mucosal barrier’s steady state induced by intestinal epithelial cells (IECs)’ abnormal apoptosis is the important pathological mechanism of this disease, while the PERK-eIF2α-CHOP signaling pathway activated by overstate of endoplasmic reticulum stress may be involved in this pathological process. Based on the previous study, which we found that Gancao Xiexin Decoction has advantages on the treatment of UC and it can inhibit the expression of GRP78、eIF2α and CHOP, this study focuses on the PERK-eIF2α-CHOP signaling pathway which is closely related to cell apoptosis. We plan to determine the scientific hypothesis that Gancao Xiexin Decoction can inhibit IECs’ abnormal apoptosis, protect the intestinal mucosal barrier and treat UC through blocking up the PERK-eIF2α-CHOP signaling pathway. Firstly, by using IECs’ endoplasmic reticulum stress model as research subject, we try to clarify the mechanism of Gancao Xiexin Decoction affecting IECs’ abnormal apoptosis by regulating the PERK-eIF2α-CHOP signaling pathway; secondly, by using UC rat model, we try to further demonstrate the therapeutic effect of Gancao Xiexin Decoction to protect intestinal mucosal barrier’s damage in UC by suppressing the activation of PERK-eIF2α-CHOP signaling pathway. Therefore, our study aims to further improve the pathological mechanism of UC, while the final results of our research may provide new insight to the TCM treatment of UC and the experiment basis for its deeper drug development.

溃疡性结肠炎（UC）是消化科常见病，治疗较为困难。研究发现，肠上皮细胞（IECs）异常凋亡引起肠黏膜屏障稳态破坏是该病的重要病理机制，而内质网应激过度下激活的PERK-eIF2α-CHOP信号通路可能参与了此过程。在我们临床发现甘草泻心汤治疗UC具有优势，前期研究提示甘草泻心汤能抑制GRP78、eIF2α和CHOP表达的基础上，本项目紧扣与细胞凋亡密切相关的PERK-eIF2α-CHOP通路，从甘草泻心汤可能通过抑制该通路而抑制IECs异常凋亡、保护肠黏膜屏障从而治疗UC的科学假说出发，首先以IECs内质网应激模型为研究对象阐明甘草泻心汤调控该通路而影响IECs凋亡的机制，其次以UC小鼠模型为研究对象明确甘草泻心汤抑制该通路活化而改善肠黏膜屏障损伤在UC中的治疗作用。通过本研究将进一步完善UC的病理机制研究，并为中医药治疗UC提供新的实验依据，为其药物深层次开发提供实验基础。

溃疡性结肠炎（UC）是发病率日趋升高的消化系统慢性病，治疗较为困难。研究发现，肠上皮细胞（IECs）异常凋亡引起肠黏膜屏障稳态破坏是该病的重要病理机制，而内质网应激过度下激活的PERK-eIF2α-CHOP信号通路可能参与了此过程。本项目紧扣与细胞凋亡密切相关的PERK-eIF2α-CHOP通路，选择具有确切临床疗效和补充治疗优势的中药复方甘草泻心汤，从甘草泻心汤可能通过抑制PERK-eIF2α-CHOP通路来抑制IECs异常凋亡、保护肠黏膜屏障从而治疗UC的科学假说出发，首先以体外肠细胞的内质网应激模型为研究对象阐明甘草泻心汤调控该通路而影响IECs凋亡的机制，其次以小鼠UC模型为研究对象明确甘草泻心汤抑制该通路活化而改善肠黏膜屏障损伤在UC中的治疗作用，最后在蛋白表达和基因转录层面揭示PERK和CHOP分别是该通路上下游信号转导的关键靶点。. 本研究结果显示：UC肠黏膜屏障损伤可能与PERK-eIF2α-CHOP信号通路的活化转导有关，即UC时IECs处于过度内质网应激状态，细胞内PERK-eIF2α-CHOP信号通路被激活、信号依次传递至CHOP，后者通过调控一系列凋亡效应蛋白的表达而引起IECs异常凋亡、肠上皮通透性增加；PERK和CHOP分别是该通路上下游信号转导的关键靶点。而甘草泻心汤对UC具有良好的治疗效果，其对UC肠黏膜屏障的保护作用可能是通过抑制PERK-elF2α-CHOP凋亡信号通路的活化转导，从而减少IECs凋亡、降低肠上皮通透性而实现的。本研究结果对补充完善UC复杂的发病机制，为中医药对UC的临床应用提供客观的实验依据，为其药物深层次开发提供实验基础。