H. Pylori infection is one of the most common infections of man and it disproportionately affects the economically disadvantaged throughout the world. Infected individuals typically have lifelong gastritis that can culminate in ulcer disease, gastric atrophy, and epithelial DNA damage leading to gastric cancer. The overall hypothesis of this proposal is that H. Pylori and its products result in a deleterious cellular response that causes DNA damage and cancer. In previously published and preliminary work both in vivo and in vitro, my mentor~s laboratory has shown that gastric cancer is associated with a high frequency of microsatellite instability, a hallmark of defective DNA mismatch repair (MMR). I will test the hypothesis that DNA mismatch repair is modulated by H. Pylori products. I will evaluate the regulation by H. Pylori products. I will evaluate the regulation H. Pylori of the expression of mismatch repair genes such as hMSH2. H. Pylori bacteria and lysates from defined (cag A and vacA genotyped) strains will be used to stimulate cells and biopsies obtained from HP- infected and non-infected donors. I will use a quantitative functional DNA mismatch repair reporter system to test the effects of H. Pylori products on DNA mismatch repair in gastric epithelial cells in vitro. The results of these studies should provide novel information that will elucidate the central carcinogenetic steps of H. Pylori disease and will provide potential new targets for intervention and therapy.
