高原环境因素对幽门螺杆菌诱导胃上皮细胞自噬的调控及机制研究

Helicobacter pylori (H. pylori) infection plays a crucial role in the pathogenesis of gastric cancer, and the high incedence of H. pylori infection in the plateau of China might be attributed to special environmental factors. It is suggested that H. pylori can invade and replicates within intracellular compartments of gastric epithelial cells, which autophagy plays an important role in the processes. In the study, we will research H. pylori-infected gastric epithelial models and animal models and H. pylori-infected population, use experimental methods and technologies including laser scanning confocal microscope, fluorescence in situ hybridization, transmission electron microscopy, microRNAs chips, Western blot, gene knock-out and live cell imaging. We would clarify that the impact of plateau environmental factors on H. pylori-induced autophagy in gastric epithelial cells based on the molecular, cell and tissue. To investigate plateau environmental factors (temperature, humidity, pH value, atmospheric pressure, oxygen concentration, salt concentration) regulates H. pylori-induced autophagy in gastric epithelial cells and affects the intracellular fate of H. pylori. We would research the sequential responding model (plateau environment factors - H. pylori - vacA/cagA – microRNAs - autophagy) and clarify the molecular mechanism of H. pylori-induced autophagy in gastric epithelial cells. This study would be expected to provide new insights into improving the preventive and therapeutic effect of H. pylori infection.

幽门螺杆菌感染与胃癌的发生密切相关，而高原地区幽门螺杆菌的高感染率与其特殊环境存在潜在联系。研究表明幽门螺杆菌能侵入到胃粘膜上皮细胞内并长期存活，宿主细胞的自噬在其中扮演着重要作用。本项目拟通过高原环境下幽门螺杆菌感染的细胞模型、动物模型和感染人群，运用激光共聚焦显微镜、荧光原位杂交、透射电镜、microRNAs芯片、Western blot、基因敲除和活细胞成像等方法，从分子、细胞和组织水平，阐明高原环境因素在幽门螺杆菌诱导胃上皮细胞自噬与感染过程中的作用，揭示高原环境因素（温度、湿度、pH值、大气压、氧浓度、盐浓度）对幽门螺杆菌诱导胃上皮细胞自噬的调控，以及对入侵细胞内的幽门螺杆菌存活的影响。探讨“高原环境因素–幽门螺杆菌–vacA/cagA–microRNAs–自噬”的作用模式，深入研究高原环境下幽门螺杆菌诱导胃上皮细胞自噬的分子机制，从而为高原地区幽门螺杆菌感染的防治提供理论依据。

幽门螺杆菌感染与胃癌的发生密切相关，而胃癌高发区幽门螺杆菌的高感染率与其特殊环境存在潜在联系。研究表明幽门螺杆菌能侵入到胃粘膜上皮细胞下层并长期定植，幽门螺杆菌分泌的毒素cagA在宿主细胞的自噬中扮演着重要作用。本项目拟通过分子水平、细胞水平、动物水平来分析幽门螺杆菌感染与肿瘤自噬之间的关系。项目组对来自甘肃省胃癌高发区的临床菌株进行了分离培养，并基于cgMLST分型鉴定出新的分子亚型；在项目的过程中我们还研究发现了CYP3A4的表达可能与慢性萎缩性胃炎向胃癌的潜在致癌转化有关；项目组团队在建立幽门螺杆菌动物模型中采用了交叉学科方法，制备近红外量子点对幽门螺杆菌进行了标记，并在小鼠体内实现了可视化的示踪，为进一步研究奠定了基础。. 项目组的研究，幽门螺杆菌感染与自噬的文章还没有最后发表，但是在项目执行期内，我们发现了甘肃省胃癌高发区单独与的幽门螺杆菌东亚株以外的菌株，并且发现了CYP3A4分子标志物以及可视化动物模型的建立，这些研究成果对揭示幽门螺杆菌感染的机制都有重要的意义，并对胃癌高发区的幽门螺杆菌的防治提供了新的思考。