探讨Notch信号通路在健脾益气方促进CAG胃粘膜细胞增殖中的调控机制

Chronic atrophic gastritis (CAG) is a kind of refractory digestive system disease and the specfic drugs on improving gastric mucosa atrophy are scarce in clinical practice. Previous clinical trials have showed that Jianpiyiqi Formula treated CAG effectively. According to the results of pre-experiment, our research group has found that Jianpiyiqi Formula improved gastric mucosal atrophy and activated the expression of Notch signaling pathway ralated proteins and genes in CAG rats significantly. However, the molecular pharmacological mechanisms of CAG treated by Jianpiyiqi Formula are need to study further systemically. Recent studies have found that the inhibiton of gastric mucosal cell proliferation is closely related to the pathogenesis of CAG, and Notch signaling pathway plays a key role in regulation of gastric mucosal cell proliferation. Therefore, our research group puts forward the scientific hypothesis that Jianpiyiqi Formula has the curative effect on CAG by regulating the Notch signaling pathway and then promoting gastric mucosal cell proliferation. CAG rat model and gastric mucosal GES-1 cell injury model will be established in this study. The regulatory mechanisms, which Jianpiyiqi Formula promote gastric mucosal epithelial cell proliferation via Notch signaling pathway in CAG rats, will be studied systematically by designing the animal, cellular and molecular experiments. The aim of this research is to explain the molecular pharmacological mechanisms of CAG treated by Jianpiyiqi Formula via Notch signaling pathway. The research will provide scientific evidence for clinical application of Jianpiyiqi Formula.

慢性萎缩性胃炎（CAG）为难治性消化系统疾病，在临床上缺乏改善胃粘膜萎缩的特效药物。前期临床研究证实健脾益气方能有效治疗CAG，本课题组通过预实验发现健脾益气方能明显改善CAG大鼠胃粘膜萎缩，促进胃粘膜组织中Notch信号通路相关蛋白和基因的表达，但其分子药理机制尚待系统研究。最新研究报道CAG发生与胃粘膜细胞增殖的阻滞密切相关，Notch信号通路在调控胃粘膜细胞增殖中起关键作用。因此，本课题组提出了“健脾益气方可能通过激活Notch信号通路，促进胃粘膜细胞增殖，从而对CAG发挥疗效”的科学假说。本项目拟通过建立CAG大鼠模型和胃粘膜GES-1细胞损伤模型，在动物、细胞和分子水平上，系统研究Notch信号通路在健脾益气方促进CAG胃粘膜细胞增殖中的调节作用。本项目旨在从Notch信号通路的角度，阐释健脾益气方治疗CAG的分子药理机制，为健脾益气方的临床应用提供科学依据。

慢性萎缩性胃炎（chronic atrophic gastritis，CAG）是一种消化系统常见的疑难病，CAG伴随肠化和上皮内瘤变等病理状态被称为胃癌前病变（gastric precancerous lesion，PLGC），与胃癌（gastric cancer，GC）的发生密切相关。临床上一直缺乏公认有效的治疗CAG的药物。近年来大量临床研究表明，中医药对CAG具有优势疗效。因此，深入研究中医药改善CAG的分子药理机制具有重要的临床应用价值。健脾益气方来源于香砂六君子汤，具有健脾益气、活血行气的功效。前期通过随机、双盲、双模拟、多中心临床研究表明健脾益气方能够改善CAG患者临床症状和胃粘膜萎缩病理状态。最新研究报道CAG发生与胃粘膜细胞增殖的阻滞密切相关，Notch信号通路在调控胃粘膜细胞增殖中起关键作用。因此，本项目以Notch信号通路为角度来阐释健脾益气方的药理机制。本项目通过构建液相质谱联用技术（UPLC-ESI-Q-TOF-MS/MS）指纹图谱，研究了健脾益气方的物质基础和药物质量控制。本项目通过建立甲基硝基亚硝基胍（methyl-nitro-nitrosoguanidine，MNNG）诱导的CAG大鼠模型，研究发现健脾益气方能够改善大鼠胃粘膜萎缩病理，上调胃粘膜保护因子，增加大鼠胃组织中Notch信号通路的表达，影响大鼠肠道微生态的变化。本项目通过建立MNNG诱导的人胃粘膜上皮GES-1细胞损伤模型，通过运用病毒质粒基因干扰技术，构建Notch1基因干扰的胃粘膜细胞损伤模型，研究发现健脾益气方含药血清在一定程度上能够保护胃粘膜细胞的化学损伤，增加损伤的胃粘膜细胞中Notch信号通路的表达。总之，本项目为研究CAG胃粘膜萎缩的分子病理机制提出了新观点，为阐释健脾益气方治疗CAG的分子药理机制提供了新视野，为健脾益气方治疗CAG的临床应用提供了新证据。