Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. Helicobacter pylori is the strongest identified risk factor fr this malignancy, yet only a fraction of colonized persons ever develop neoplasia. One H. pylori determinant associated with increased gastric cancer risk is the cag pathogenicity island, and several cag genes encode components of a type IV secretion system which exports bacterial proteins such as CagA into host epithelial cells. Our group has now demonstrated that H. pylori cag+ strains selectively activate -catenin, the EGF receptor (EGFR), and spermine oxidase (SMO), host effectors that influence carcinogenesis, in gastric epithelial cells. We have also demonstrated that environmental factors associated with gastric cancer, such as iron deficiency and salt, augment the ability of H. pylori cag+ strains to induce gastric cancer. Therefore, the overarching objective of this Application is delineation of the molecular signaling events initiate by H. pylori:epithelial cell contact that regulate phenotypes related to gastric carcinogenesis. This PPG will integrate studies of host-pathogen interactions initiated by biomedical researchers who have made a strong and clear commitment to research within the fields of gastroenterology, cancer biology, carcinogenesis, and microbiology, and will generate results that would not be attainable through independent investigation. The component Projects are driven by discrete hypotheses, yet are cohesive in that each focuses on H. pylori:epithelial interactions that induce cellular responses with carcinogenic potential. The individual projects include: Project 1. Role of iron and -catenin activation in gastric carcinogenesis (Pi-Richard Peek). Project 2. EGFR activation and polyamines in H. pylori-induced gastric cancer (Pi-Keith T. Wilson). Project 3. Regulation of H. pylori virulence by dietary factors that impact gastric cancer (Pi-Timothy Cover). The efforts of each Project will be further unified by dynamic interactions with Specific Core facilities, which include the Gastric Histopathology Core (Core A), the Proteomics Core (Core B), and an Administrative Core (Core C). By maintaining a grounded focus on fundamental interactions that occur at the H. pylori:epithelial interface, results from this proposal will not nly improve our understanding of gastric cancer, but will also identify potential therapeutic targets for prevention and more effective treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA116087-10
Application #
9203563
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Daschner, Phillip J
Project Start
2005-07-01
Project End
2018-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G et al. (2017) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut :
Hardbower, Dana M; Asim, Mohammad; Luis, Paula B et al. (2017) Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc Natl Acad Sci U S A 114:E751-E760
Gobert, Alain P; Wilson, Keith T (2017) Effect of CO2 on Peroxynitrite-Mediated Bacteria Killing: Response to Tsikas et al. Trends Microbiol 25:602-603
Kyburz, A; Urban, S; Altobelli, A et al. (2017) Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy. Clin Exp Allergy 47:1331-1341
Varga, Matthew Gordon; Peek, Richard M (2017) DNA Transfer and Toll-like Receptor Modulation by Helicobacter pylori. Curr Top Microbiol Immunol 400:169-193
Feichtinger, René G; Neureiter, Daniel; Skaria, Tom et al. (2017) Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis. Oxid Med Cell Longev 2017:1320241
Loh, John T; Beckett, Amber C; Scholz, Matthew B et al. (2017) High salt conditions alter transcription of Helicobacter pylori genes encoding outer membrane proteins. Infect Immun :
Kim, Aeryun; Servetas, Stephanie L; Kang, Jieun et al. (2017) Correction: Helicobacter pylori bab Paralog Distribution and Association with cagA, vacA, and homA/B Genotypes in American and South Korean Clinical Isolates. PLoS One 12:e0176468
Xiong, Menghua; Bao, Yan; Xu, Xin et al. (2017) Selective killing of Helicobacter pylori with pH-responsive helix-coil conformation transitionable antimicrobial polypeptides. Proc Natl Acad Sci U S A 114:12675-12680
Zhu, Shoumin; Soutto, Mohammed; Chen, Zheng et al. (2017) Helicobacter pylori-induced cell death is counteracted by NF-?B-mediated transcription of DARPP-32. Gut 66:761-762

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