Project 3: Regulation of H. pylori Virulence by Dietary Factors That Impact Gastric Cancer

项目3摘要 革兰氏阴性细菌幽门螺杆菌在人胃中的持续定植是 与胃腺癌发生风险显著增加相关。胃癌是一种 是全球癌症相关死亡的第三大原因，H.幽门螺杆菌已被归类为I型致癌物 由世界卫生组织。在H.幽门螺杆菌感染的人，胃癌的风险是由 多个变量，包括H。幽门螺杆菌菌株特异性毒力成分，宿主遗传特征， 环境因素这项工作的长期目标是确定H。幽门 感染可能导致胃癌，并开发改进的方法来识别患有胃癌的个体。 胃癌的风险增加，因此他们可以作为治疗干预的目标。在以前的研究中 在项目1中，我们已经证明高盐饮食会增加H.幽门感染 沙鼠我们现在建议确定高盐饮食增强H的机制。幽门螺杆菌毒力和 增加胃癌风险。目的1将定义高盐饮食调节胃肠道功能的机制。 粘膜炎症反应，使用蒙古沙鼠和小鼠模型。目标2将检测胃和 血液变化是胃癌前病变的标志物，使用成像质谱， 代谢组学技术。目的3将确定高盐饮食对H.幽门螺杆菌菌株， 增强致癌潜力！这些目标将与项目1和项目2中提议的工作相互交织， 利用胃组织学和蛋白质组学和代谢组学核心。这些研究将 导致重要的进展，在我们的理解的分子机制，H。hp感染与 高盐饮食促进胃癌的发展。最终，这些研究应该会带来进步， 在预防和治疗慢性炎症环境中发生的恶性肿瘤中的应用。 !

Project 3 Summary Persistent colonization of the human stomach with the Gram-negative bacterium Helicobacter pylori is associated with a marked increase in risk for the development of gastric adenocarcinoma. Gastric cancer is the third 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 H. pylori strain-specific virulence constituents, 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 so they can be targeted for therapeutic intervention. In previous studies with Project 1, we have shown that a high-salt diet increases the risk of gastric cancer in H. pylori-infected gerbils. We now propose to define the mechanisms by which a high salt diet enhances H. pylori virulence and increases gastric cancer risk. Aim 1 will define mechanisms by which a high salt diet modulates the gastric mucosal inflammatory response, using both Mongolian gerbil and mouse models. Aim 2 will detect gastric and blood alterations that are markers of gastric premalignant conditions, using imaging mass spectrometry and metabolomics techniques. Aim 3 will define effects of a high salt diet on selection of H. pylori strains with enhanced carcinogenic potential.!These aims will interdigitate with work proposed in Projects 1 and 2 and will utilize both the Gastric Histopathology and the Proteomics and Metabolomics Cores. These studies will lead to important advances in our understanding of the molecular mechanisms by which H. pylori infection and a high salt diet 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. !