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. !