Helicobacter pylori is the strongest identified risk factor for gastric cancer and contact between H. pylori and epithelial cells dysregulates signaling pathways that influence oncogenesis. Thus, our long-term objective is to define molecular pathways induced by pathogenic H. pylori that lead to epithelial responses with carcinogenic potential. We have shown that H. pylori utilizes decay accelerating factor (DAF) as an epithelial receptor, increases its expression in vitro and in vivo, and that DAF deficiency attenuates injury in infected mice. One H. pylori strain-specific determinant that augments cancer risk is the cag pathogenicity island, which translocates peptidoglycan into host cells leading to Nod1 activation. In studies supported by R01 58587, we demonstrated that a rodent-adapted derivative (7.13) of a human H. pylori cag+ strain (B128) rapidly induces gastric cancer in rodents. Utilizing 2D-DIGE and mass spectrometry, we found that the H. pylori protein HP0310 exists as different isoforms in strain 7.13 versus B128. HP0310 deacetylates peptidoglycan, which has focused our current studies on the role of peptidoglycan as a virulence constituent. We now demonstrate that disruption of peptidoglycan synthesis attenuates epithelial cell migration and proliferation in response to H. pylori and abolishes H. pylori-induced DAF expression. H. pylori infection rates typically parallel the prevalence of gastric cancer in specific regions;however, this association is not universal. We have now expanded the scope of our work in collaboration with Dr. Pelayo Correa by examining H. pylori isolates harvested from individuals who reside in either a high-risk or a low-risk region of gastric cancer in Colombia. These studies will allow us to determine if strains harvested from subjects with an enhanced risk for gastric cancer induce carcinogenic epithelial responses. Our hypothesis is that strain-specific proteins expressed by carcinogenic H. pylori aberrantly activate cellular phenotypes that influence disease. Therefore, our specific aims are to: 1. Define pathologic epithelial responses to carcinogenic H. pylori mediated by Nod1 activation. 2. Define alterations in DAF expression that are mediated by Nod1 activation. 3. Determine the role of Nod1 in regulating host inflammatory and injury responses to H. pylori using in vivo and ex vivo genetic models of Nod1 deficiency.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Hamilton, Frank A
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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