(taken from the application) H. pylori infection of the stomach causes chronic gastritis, and epidemiological studies have demonstrated that H. pylori is an independent risk factor for gastric cancer. However, the mechanisms by which H. pylori causes epithelial cell injury, or leads to the development of gastric cancer is not well understood. People infected with H. pylori have a 3 to 9 fold higher risk of developing gastric cancer than non-infected persons. Progression from superficial gastritis caused by H. pylori to atrophic gastritis with intestinal metaplasia is felt to be a precursor to gastric cancer development. Investigators have postulated that the natural progression of H. pylori-associated chronic gastritis is to atrophic gastritis, which may be prolonged or shortened by bacterial factors that can modulate gastric epithelial defense mechanisms. H. pylori strains that possess the cag pathogenicity island are more strongly associated with gastric cancer, than those that do not (cagA-negative strains). H. pylori has been shown to induce oxidative bursts from macrophages and there is increased iNOS and peroxynitrite in the gastric mucosa in infected persons, along with less vitamin C. We postulate that H. pylori may increase the risk of gastric cancer by interacting with specific transcription factors (NF-kappaB, p53) resulting in a relative resistance to apoptosis with cagA positive strains. This grant is part of an interactive R01/R29 grant proposal to elucidate interactions between H. pylori and transcription factors NF- kB and p53, in vitro and in vivo, which may impact negatively on apoptosis and lead to increased cancer risk from exposure to chemical carcinogens and reactive oxygen species.
The specific aims of this proposal are: (1) to determine if the differential regulation of p53 by cagA-positive as opposed to cagA-negative strains results in arresting cells at different phases of the cell cycle; (2) To determine if activation of NF-kB by cagA-positive strains is associated with decreased apoptosis in response to H. pylori cell injury, and whether or not this involves inhibition of p53 dependent pathways of apoptosis and/or stimulation of bc1-2. Studies will also look at the potential impact of iNOS stimulation in preventing apoptosis in this setting. Our experiments will utilize human gastric epithelial cells and include primary cultures of normal human gastric epithelial cells and an SV-40 transformed non-malignant human gastric epithelial cell line. In vivo studies will be performed as part of this interactive R01/R29 proposal by Dr. Peek, who will use established animal models which can be infected with H. pylori. These studies will elucidate pathways within gastric cells which can be altered by H. pylori and show potential mechanisms by which this bacteria may increase the susceptibility of gastric epithelial cells to DNA damage from carcinogens.
