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

幽门螺杆菌在人类胃部持续定植革兰氏阴性杆菌会增加患胃腺癌的风险。胃癌是全球第二大癌症相关死亡原因，世界卫生组织已将幽门螺杆菌列为I型致癌物质。在幽门螺杆菌感染者中，患胃癌的风险是由多个变量决定的，包括幽门螺杆菌菌株的特征、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杆菌感染导致胃癌的机制，并开发改进的方法来识别患胃癌风险增加的个人。在以前的研究中，我们已经证明感染了GagA阳性幽门螺杆菌菌株的人比感染GagA阴性菌株的人患胃癌的风险更高。在蒙古沙土鼠模型中，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增加了感染幽门螺杆菌的沙土鼠患胃癌的风险。此外，我们还表明，幽门螺杆菌暴露在高盐条件下会刺激GagA的产生上调。在这个项目中，我们建议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。目的1研究三种盐调控的幽门螺杆菌外膜蛋白(HopQ和两种VacA样蛋白)在胃癌发生中的作用。我们将使用多种实验方法，包括常规细胞培养、胃器官培养和胃器官培养，以及幽门螺杆菌诱导的蒙古沙土鼠胃癌模型。目的2将确定在幽门螺杆菌感染的沙土鼠模型中，高盐饮食和低铁饮食增加胃癌风险的共同途径的特征。目的3将分析体内盐反应幽门螺杆菌基因的调节，并分析幽门螺杆菌对致癌胃环境的适应。这些目标将与项目1和2中提出的工作交叉(每个项目都侧重于幽门螺杆菌诱导的上皮细胞改变)，并将利用胃组织病理学和蛋白质组学核心。这些研究将有助于我们理解幽门螺杆菌感染和相关饮食因素促进胃癌发生的分子机制。最终，这些研究将导致在慢性炎症背景下发展的恶性肿瘤的预防和治疗方面的进展。

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.