(taken from the application) 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. There is now substantial evidence that these outcomes are the result of a complex interplay of multiple different H. pylori gene products with the gastric epithelium and mucosal immune and inflammatory systems. The co-investigators of this proposal have an ongoing interest in three distinct but interrelated aspects of H. pylori disease: the immune response, inflammation, and gastric cancer. In our previously published and preliminary work both in vivo and in vitro, we have shown that H. pylori directly induces an immune response skewed towards Th1 mediators, that H. pylori upregulates production of the inflammatory mediators nitric oxide (NO) and prostanoids, and that gastric cancer is associated with a high frequency of microsatellite instability, a hallmark of defective DNA mismatch repair (MMR). We suggest that the products of H. pylori induce an immune and inflammatory response program that is maladaptive, in that it does not eliminate the pathogen and at the same time causes tissue injury and epithelial DNA damage. Our proposal will test the following specific aims:
The first aim will test the hypothesis that H. pylori products induce expression of critical immune and inflammatory mediators, such as cytokines, NO, and prostaglandins that counter-regulate each other and regulate mismatch repair genes such as hMSH2.
The second aim will be to directly test the hypothesis that H. pylori products and immune and inflammatory mediators contribute to genetic instability characteristic of gastric cancer, using a quantitative functional DNA mismatch reporter system and sensitive micromethod for DNA repair status. The results of these studies will provide new information that will elucidate the central pathogenetic steps of H. pylori disease and will provide potential new targets for intervention and therapy.
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