Molecular and genetic analysis of the hielcobacter pylori virulence Factor CagA

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DESCRIPTION (provided by applicant): Helicobacter pylori infects over half the world's population and is associated with a broad range of gastric maladies including gastritis, peptic ulcer disease, and gastric cancer. Pathogenic strains of H. pylori contain the cag pathogenicity island that encodes a type IV secretion system capable of translocating the bacterial effector protein CagA into host cells. Inside the host cell, CagA binds to a number of host proteins including the phosphatase SHP-2. The molecular pathways activated by CagA in host cells, both dependent and independent of SHP-2, are not well understood. The long-term goal of this project is to determine the mechanisms by which CagA's molecular activity within host cells leads to disruption of host cell signal transduction, loss of epithelial integrity, and ultimately the promotion of carcinogenesis. We have developed a transgenic Drosophila model to study CagA's activity in the retinal epithelium, which is both a model for SHP-2 signal transduction and for epithelial organization. CagA expression in this tissue induces developmental defects that both mimic activation of SHP-2 (specification of excess photoreceptors) and are distinct from SHP-2 activation (disruption of the epithelium and photoreceptor microvilli). In parallel studies we have demonstrated that CagA causes disruption of microvilli in H. pylori infected cultured gastric epithelial cells. Using these two complementary systems, we propose to address the following specific aims: 1. Test the hypothesis that CagA has SHP-2 independent activities in eukaryotic tissues. 2. Test the hypothesis that CagA disrupts epithelial cell microvilli independently of SHP-2 function. 3. Identify genes that mediate CagA function in eukaryotic cells. Stomach cancer is the second leading cause of cancer death worldwide. Over half of all stomach cancers are thought to be caused by infection with the bacterium H. pylori. During H. pylori infection the bacteria translocate a protein, CagA, into stomach cells, which causes changes in the cells that promote cancer. We propose to determine the molecular basis for CagA's effects on stomach cells as a ways to better understand, diagnose, and treat stomach cancer.