Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and Helicobacter pylori is the strongest identified risk factor for this malignancy, yet only a fraction of colonized persons ever develop neoplasia. One H. pylori determinant associated with gastric cancer 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 and the EGF receptor (EGFR), host effectors that influence carcinogenesis, in gastric epithelial cells. We have also demonstrated that an environmental factor associated with gastric cancer, salt, augments the ability of H. pylori cag+ strains to induce aberrant epithelial responses. Therefore, the overarching objective of this Application is delineation of the molecular signaling events initiated 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. Mechanisms that regulate Helicobacter pylori-induced ?-catenin activation (PI-Richard Peek). Project 2. EGFR activation in H. pylori-induced gastric cancer (PI-Brent Polk). Project 3. Helicobacter pylori cag pathogenicity island and gastric carcinogenesis (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 only improve our understanding of gastric cancer, but will also facilitate identification of 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 #
5P01CA116087-05
Application #
8413056
Study Section
Special Emphasis Panel (ZCA1-GRB-S (O1))
Program Officer
Daschner, Phillip J
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,252,598
Indirect Cost
$436,573
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
Hardbower, Dana M; Singh, Kshipra; Asim, Mohammad et al. (2016) EGFR regulates macrophage activation and function in bacterial infection. J Clin Invest 126:3296-312
Riquelme, Ismael; Tapia, Oscar; Leal, Pamela et al. (2016) miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway. Cell Oncol (Dordr) 39:23-33
Gogoi, Mayuri; Datey, Akshay; Wilson, Keith T et al. (2016) Dual role of arginine metabolism in establishing pathogenesis. Curr Opin Microbiol 29:43-8
Gobert, Alain P; Wilson, Keith T (2016) The Immune Battle against Helicobacter pylori Infection: NO Offense. Trends Microbiol 24:366-76
Beceiro, S; Radin, J N; Chatuvedi, R et al. (2016) TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection. Mucosal Immunol :
Zhao, Gang; Liu, Liping; Peek Jr, Richard M et al. (2016) Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth. J Biol Chem 291:20462-72
Peek Jr, Richard M (2016) New Biology to New Treatment of Helicobacter pylori-Induced Gastric Cancer. Dig Dis 34:510-6
Chen, Jinjing; Wang, Zhen; Hu, Xiangming et al. (2016) BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation. J Immunol 196:4132-42
Amieva, Manuel; Peek Jr, Richard M (2016) Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 150:64-78
Varga, Matthew G; Piazuelo, M Blanca; Romero-Gallo, Judith et al. (2016) TLR9 activation suppresses inflammation in response to Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol 311:G852-G858

Showing the most recent 10 out of 166 publications