Helicobacter pylori infection is the single most common cause of duodenal and gastric ulcers. The infection is also associated with the development of gastric adenocarcinoma. There is an urgent need to control the incidence of H. pylori disease with twenty five million Americans currently suffering from ulcer disease and related complications, more than one million annual hospitalizations, over 50,000 surgeries, $500 million dollars in health care costs and at least 6,000 deaths associated with the infection. The designing of effective and reliable intervention strategies, however, requires among other factors a detailed understanding of the pathogenesis of the disease. Despite what is presently known about the early acquisition and establishment of chronic H. pylori infection, the pathogenesis of H. pylori-induced ulcer or gastric carcinoma is unclear. Recent reports have implicated nitric oxide in the pathogenesis of lesion formation in H. pylori infections in both humans and mice, but definitive studies have yet to directly link nitric oxide to H. pylori- induced pathology. The focus of this proposal is to use novel in vitro and in vivo models of Helicobacter infection, for both ulcer and carcinoma development, using normal and genetically engineered mice deficient in the production of inducible nitric oxide. Using molecular biological and tissue culture techniques, we propose to determine: 1) whether nitric oxide is involved in ulcer or tumor development, 2) how nitric oxide affects susceptibility to Helicobacter infection, 3) what cell populations produce nitric oxide during a Helicobacter infection and to begin characterizing specific Helicobacter proteins inducing nitric oxide, 4) the likely biological processes induced by nitric oxide to cause lesion development. These studies will contribute to a better understanding of the mechanism of H. pylori-induce gastric ulcer and carcinoma that could lead to the design of rational therapeutic regimens to prevent lesion development.