Helicobacter pylori is a chronic infection that affects 50% of the world's population causing gastritis in all infected while only a subset develop disease of the epithelium in the form of ulceration or adenocarcinoma. Both bacterial and host factors appear to play a role in the pathogenesis of these human diseases but the specific mechanisms remain unclear. H. pylori and cytokines known to be increased in H. pylori infection, induce alterations of gastric epithelial cell growth such as the induction of programmed cell death. Phagocytic leukocytes recruited to the gastric mucosa during infection become activated, generating reactive oxygen species (ROS) that we have shown to alter gastric epithelial cell growth and induce apoptosis. Infection with H. pylori also induces the accumulation of ROS in gastric epithelial cells that may be dependent on bacterial genotype. Gastric epithelial cells respond to oxidative stress with the initial generation of ROS and subsequent activation of a redox-sensitive signaling pathway which has been shown to control the transcription of genes that regulate cell growth, repair and death processes. Of particular interest is ROS-induced activation of apurinic/apyrimidinic endonuclease-1 (AP endonuclease), a multifunctional protein that is the rate-limiting enzyme in the DNA base excision repair pathway of oxidative lesions, which also activates transcription factors including activator protein (AP)-1, and p53. Thus, the general hypothesis underlying this proposal is that oxidative stress contributes to the epithelial cell injury that occurs during H. pylori infection. The specific hypothesis that H. pylori infection stimulates redox-sensitive signaling through AP endonuclease that leads to apoptosis in gastric epithelial cells will be examined in the following specific aims:
Aim 1. Evaluate oxidative stress in gastric epithelial cell injury (apoptosis) during H. pylori infection;
Aim 2 Determine if H. pylori regulates the expression and function of AP endonuclease in gastric epithelial cells;
Aim 3. Define how AP endonuclease regulates apoptosis and the transcription of pro-apoptotic genes. These studies in cultured human cell lines and human tissue will address unanswered questions regarding the effect of oxidative stress on gastric epithelial cell injury. The molecular mechanisms governing the epithelial response to oxidative stress will also be defined. This new knowledge will improve our understanding of the pathogenesis of epithelial cell damage associated with H. pylori infection and help identify strategies for the prevention and treatment of human gastric disease.
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