Chronic gastritis induced by Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, the second leading cause of cancer-related death in the world, yet only a fraction of infected persons ever develop malignancy. Adherence of H. pylori to gastric epithelial cells is critical for induction of gastric injury;therefore, our long-term objective is to investigate the molecular pathways induced by pathogenic H. pylori that lead to epithelial responses with carcinogenic potential. Rodent models have provided valuable insights into the etiologic factors involved in gastric carcinogenesis. However, the infrequency and prolonged time-course required for development of cancer in animal models of H. pylori infection has precluded large-scale analyses that evaluate effects of both pathogen and host in the carcinogenic cascade. Our preliminary studies now demonstrate that a rodent-adapted derivative (7.13) of a human H. pylori strain (B128) rapidly induces gastric cancer in Mongolian gerbils by 4 weeks and in hypergastrinemic (INS-GAS) mice by 24 weeks. Oncogenic H. pylori strain 7.13 binds more avidly to gastric epithelial cells than its parental isolate B128, and using a proteomics-based approach, we have now identified strain-specific membrane-bound proteins expressed by H. pylori strain 7.13, which may contribute to carcinogenesis by functioning as adhesins. A host factor that may mediate aberrant epithelial responses to H. pylori is decay-accelerating factor (DAF), a receptor for chronic pathogens that orchestrates pro-inflammatory epithelial responses. Expression of DAF is increased within H. pylori-infected versus uninfected human gastric tissue, and the intensity of DAF expression is directly related to colonization density and severity of gastritis. We now show that H. pylori adheres more avidly to cells that stably express human DAF compared to vector controls. In vitro and in vivo, H. pylori induces up-regulation of DAF in gastric epithelial cells, and genetic deficiency of DAF attenuates inflammation in H. pylori -infected mice. Our hypothesis is that adherence of H. pylori to gastric epithelial cells activates host signaling pathways that influence carcinogenesis.
Our specific aims are: 1. To define the bacterial constituents in H. pylori strain 7.13 that mediate carcinogenesis. 2. To define the role of DAF in regulating pathogenic responses to H. pylori in vitro. 3. To define the effect of DAF on H. pylori'-induced injury and carcinogenesis in vivo. This study will help to identify people who are at great risk for stomach cancer. This will greatly improve diagnosis and therapy of H. pylori infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058587-09
Application #
7925799
Study Section
Special Emphasis Panel (ZRG1-DIG-C (03))
Program Officer
Hamilton, Frank A
Project Start
2000-12-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2010
Total Cost
$305,172
Indirect Cost
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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