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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058587-11
Application #
8296501
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2000-12-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$339,300
Indirect Cost
$121,800
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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