PROGRAM PROJECT GRANT OVERALL SUMMARY Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, the fourth leading cause of cancer- related death. One H. pylori determinant that increases gastric cancer risk is the cag type IV secretion system (T4SS) which exports a bacterial oncoprotein, CagA, into host cells. Our entire group has collaboratively shown that cag+ strains selectively activate a gastric stem cell population marked by Lrig1, as well as the EGF receptor, ornithine decarboxylase, and spermine oxidase, host effectors that influence carcinogenesis. Project 2, Core A, and Core B have additionally made the discovery that a pathway contributing to gastric carcinogenesis involves reactive electrophiles and developed a novel intervention strategy using a clinically available electrophile scavenger. Projects 1 and 3 demonstrated with Cores A and B that environmental components of the exposome associated with gastric cancer, such as iron deficiency or a high salt diet, positively select for H. pylori variants linked to increased cancer risk and augment the ability of cag+ strains to induce disease. Finally, all Projects used unbiased approaches (Core B) to identify novel host effectors that increase cancer risk, including bile acids. Our overarching Hypothesis is that differences in infecting strains, host responses, and environmental exposures such as diet affect the risk of developing gastric cancer as a consequence of H. pylori infection. To address this, our PPG integrates studies of host-pathogen interactions and oncogenic signaling initiated by biomedical researchers who have made a strong commitment to research within the fields of carcinogenesis, immunobiology, gastroenterology, and microbiology, and will generate results that would not be attainable through independent investigation. The Projects below are driven by discrete hypotheses, yet are cohesive in their focus on H. pylori-host interactions that induce cellular responses with carcinogenic potential. Project 1. Effect of iron deprivation on H. pylori-induced gastric carcinogenesis (PI-Richard Peek) Project 2. Polyamines and electrophiles in gastric cancer (PI-Keith Wilson) Project 3. Regulation of H. pylori virulence by dietary factors that impact gastric cancer (PI-Tim Cover) The efforts of each Project will be further unified by dynamic interactions with specific Core facilities, consisting of Gastric Histopathology Core A, Proteomics and Metabolomics Core B, and Administrative Core C, which includes sophisticated bioinformatics and statistics. By maintaining a grounded focus on interactions that occur at the H. pylori-host interface, results from this proposed work will not only improve our understanding of gastric cancer, but will also identify targets for prevention and more effective treatment of this devastating disease.