幽门螺杆菌VacA激活NLRP3炎症体通路致胃上皮细胞焦亡的机制研究

The chronic active gastritis induced by Helicobacter pylori (H.pylori) is the most important cause of gastric cancer. Pyroptosis is one of the cell programmed death pathways with caspase-1 activation and IL-1β secretion. Vacuolating cytotoxin (VacA) is one of the main pathogenic factors of H.pylori.Studies have shown H.pylori VacA induces pyroptosis of gastric epithelial cells.But the mechanism remains unknown.Caspase-1 which is the key molecular of pyroptosis is regulated by inflammasomes. Researches suggest NLRP3 inflammasome interacts with H.pylori. So we hypothesize that VacA induces pyroptosis of gastric epithelial cells through NLRP3 inflammatory pathway.In order to prove this hypothesis we will first observe the effect of H.pylori VacA caused pyroptosis of gastric epithelial cells. Next we will investigate how VacA regulate NLRP3 inflammatory pathway. Finanlly we will examine the efficacy of targeting caspase-1 therapy in treating H. pylori infection. The results will be helpful to provide new insights for prevention and treatment persistent gastritis in chronic H.pylori infection.

幽门螺杆菌（H.pylori）引起的慢性活动性胃炎是胃癌发生的最主要病因，焦亡是caspase-1依赖的、伴随IL-1β释放、与炎症反应密切相关的细胞死亡方式。初步证据显示H.pylrori主要致病因子空泡细胞毒素（VacA）能引起胃上皮细胞焦亡，但其机制尚不明确。焦亡的效应分子caspase-1的激活主要依赖于炎症体平台，NALP3炎症体参与了H.pylrori 所致的慢性炎症。因此本项目提出"VacA通过与NALP3炎症体分子相互作用激活该炎症体通路致胃上皮细胞焦亡"这一设想，拟先验证VacA致胃上皮细胞焦亡的效应，再通过上调或阻断NALP3炎症体通路以及研究VacA与炎症体分子的相互作用及其位点，进一步明确VacA致焦亡的分子机制，最后在动物模型中观察靶向caspase-1治疗H.pylori相关性胃炎的疗效，为阐释H.pylori慢性感染的机制和应用新的防治策略提供理论依据。

幽门螺杆菌（Hp）引起的慢性活动性胃炎是胃癌发生的最主要病因，焦亡是caspase-1依赖的、伴随IL-1β释放、与炎症反应密切相关的一种新的细胞死亡方式。HP诱导胃上皮细胞焦亡，很可能在慢性活动性胃炎的发病中发挥了重要作用。为验证这一假说，本研究首先通过形态学、生化指标、基因和蛋白的表达证实了HP引起胃上皮细胞焦亡的现象，随后通过体内外实验，上调及阻断NLRP3炎症体通路，证实了HP引起胃上皮细胞焦亡依赖于NLRP3-ASC-caspase-1的炎症体通路；最后通过基因敲除首次提出HP引起焦亡的关键毒力因子是VacA。为阐释HP引起胃粘膜慢性感染的机制提供了理论依据，也为临床干预提供了靶点。