维生素D受体对胃上皮细胞自噬的调节作用与机制及其在幽门螺杆菌感染中的意义

Helicobacter pylori (H. pylori) infection is associated with the development of numerous gastrointestinal disorders. However, the underlying mechanism has not been fully understood. Recent research suggests that impaired autophagy is an important factor for evading host immune responses, which has been implicated in the ability of H. pylori to persist in the stomach and induce gastric mucosal lesions. Vitamin D receptor (VDR) is a member of the nuclear receptor family of transcription factors, which plays an important role in the antimicrobial immune responses and autophagy regulations. We have recently observed a significant increase in the expression levels of VDR in vitro, which protected the host. In this study, we resolve to determine the role of VDR signaling in autophagy of gastric epithelial cells and its effect in H. pylori infection, both in vivo and vitro, through manipulating VDR signaling and observing corresponding change in expression of autophagy markers, intracellular bacteria activity and also gastric epithelial lesions. Furthermore, we resolve to determine if mTOR and CAMP-Beclin-1 pathway is required to mediate autophagy, through observing the effect on autophagy of gastric epithelial cells by blocking mTOR and CAMP-Beclin-1 pathway. Results of our study would help to better understand the mechanisms underlying H. pylori infection, and could provide potential drug target therapy for treating H. pylori infection and related gastrointestinal diseases.

幽门螺杆菌（H.pylori）感染与诸多胃肠道疾病的发生发展有关，其机制尚未完全阐明。近期研究发现，自噬功能受损是H.pylori逃避宿主免疫清除，在体内持续感染从而诱发胃黏膜病变的重要原因。维生素D3受体（VDR）作为一种重要的转录因子，可调控自噬，并具有抗微生物感染功能。本项目组前期体外研究证实，在H.pylori感染中VDR表达增加并起到宿主保护作用。在此基础上，本研究拟完善H.pylori感染的动物模型，通过增强或抑制VDR的表达，明确VDR对胃上皮细胞自噬的调控作用以及对H.pylori感染的影响；观察自噬调节通路mTOR和CAMP-Beclin-1中关键分子表达下调对VDR作用的影响，探讨VDR对自噬的调控作用是否通过mTOR 和CAMP-Beclin-1通路介导。本研究有助于深化对H.pylori感染机制的认识，为有效防治H.pylori感染及相关胃肠道疾病提供新的药物靶点。

维生素D受体（VDR）是一种重要的转录因子，具有抗微生物感染功能。有研究表明，VDR可调控自噬，而自噬功能受损是H.pylori在体内持续感染的可能机制。本项目组体外实验表明，在H.pylori感染的人胃粘膜细胞中，VDR表达增加并起到宿主保护作用，但具体机制尚不明确，且在H.pylori感染的动物模型中VDR是否起到作用尚无报道。在此基础上，本项目组进一步完善了H.pylori标准株NCTC11637急性感染Balb/c小鼠的动物模型，Western bolt及PCR实验显示H.pylori感染组VDR蛋白及mRNA的表达与对照组相比无显著差异；自噬相关蛋白LC3及P62的表达差异不显著。考虑到小鼠与人胃粘膜对特定H.pylori菌株的易感性、免疫反应有所不同，筛选H.pylori阳性的人胃粘膜活检样本，Western bolt实验显示VDR表达较阴性人群上调，这与体外实验结果一致；同时P62在感染组中上调，提示了在H.pylori感染中自噬过程受到抑制，同时自噬过程蛋白LC3II，LC3I的积累证实自噬过程被阻滞，这是H.pylori能够逃避宿主免疫清除，在胃内持续感染从而诱发胃炎、胃溃疡、胃癌等消化道相关的可能原因。除此以外，项目组对H.pylori感染、根除及胃癌患病数据进行数学建模，结果显示在我国无症状人群中进行H.pylori筛查及根除策略可经济、有效地预防胃癌，这为H.pylori感染防控工作的推广提供了依据。