Regulation of H. Pylori Virulance by Dietary Factors that Impact Gastric Cancer

幽门螺杆菌在人胃中的持续定植与胃腺癌发生风险增加有关。胃癌是全球癌症相关死亡的第二大原因，而幽门螺杆菌已被世界卫生组织列为I型致癌物。在幽门螺杆菌感染者中，胃癌的发生风险是由多种因素决定的，包括幽门螺杆菌菌株特征、宿主遗传特征和环境因素。这项工作的长期目标是确定幽门螺旋杆菌感染导致胃癌的机制，并开发改进的方法来识别胃癌风险增加的个体。在以前的研究中，我们已经表明，与感染gaga阴性菌株的人相比，感染gaga阳性幽门螺杆菌菌株的人患胃癌的风险增加。在蒙古沙鼠模型中，幽门螺杆菌诱导的胃癌是gaga依赖的，我们已经证明，高盐饮食和低铁饮食都会增加幽门螺杆菌感染沙鼠患胃癌的风险。此外，我们已经表明，暴露于高盐条件下的幽门螺杆菌会刺激GagA产生的上调。在本项目中，我们拟进一步研究影响胃癌的饮食因素对幽门螺杆菌毒力的调节。目标1建议定义三个角色

Persistent colonization of the human stomach with the Gram-negative bacterium Helicobacter pylori is associated with an increased risk for the development of gastric adenocarcinoma. Gastric cancer is the second leading cause of cancer-related death worldwide, and H. pylori has been classified as a type I carcinogen by the World Health Organization. Among H. pylori-infected persons, the risk of gastric cancer is determined by multiple variables, including characteristics of H. pylori strains, host genetic characteristics, and environmental factors. The long-term goal of this work is to define the mechanisms by which H. pylori infection can lead to gastric cancer, and to develop improved approaches for identifying individuals who have an increased risk for gastric cancer. In previous studies, we have shown that persons infected with GagA-positive H. pylori strains have an increased gastric cancer risk compared to persons infected with GagA-negative strains. H. pylori-induced gastric cancer in the Mongolian gerbil model is GagA-dependent, and we have shown that both a high-salt diet and a low-iron diet increase the risk of gastric cancer in H. pylori-infected gerbils. Furthermore, we have shown that exposure of H. pylori to high-salt conditions stimulates upregulation of GagA production. In this project, we propose to investigate further the regulation of H. pylori virulence by dietary factors that impact gastric cancer. Aim 1 proposes to define the roles of three salt-regulated H. pylori outer membrane proteins (HopQ and two VacA-Iike proteins) in gastric cancer development. We will use multiple experimental approaches, including conventional cell culture, gastric organ culture and gastric organoid culture, and the Mongolian gerbil model of H. pylori-induced gastric cancer. Aim 2 will identify shared .features of the pathways by which a high-salt diet and a low-iron diet augment gastric cancer risk in the H. pylori-infected gerbil model. Aim 3 will analyze regulation of salt-responsive H. pylori genes in vivo and analyze adaptation of H. pylori to a carcinogenic gastric environment. These aims will interdigitate with work proposed in Projects 1 and 2 (which each focus on H. pylori-induced epithelial cell alterations) and will utilize both the Gastric Histopathology and Proteomics Cores. These studies should lead to important advances in our understanding of the molecular mechanisms by which H. pylori infection and relevant dietary factors promote the development of gastric cancer. Ultimately, these studies should lead to advances in the prevention and therapy of malignancies that develop in the setting of chronic inflammation.