Persistent colonization of the human stomach with the Gram-negative bacterium Helicobacter pylori is associated with an increased risk for the development of gastric adenocarcinoma. H. pylori isolates from different humans exhibit a considerable level of genetic diversity. One chromosomal region that is present in some H. pylori strains but not others is the cag pathogenicity island (PAI), a 40 kb region that is predicted to encode 27 different proteins. H. pylori strains harboring the cag pathogenicity island are associated with a significantly higher rate of gastric cancer incidence than are strains that lack the cag pathogenicity island. The cag PAI encodes an effector protein, CagA, that is translocated into epithelial cells via a type IV secretion process. The long-term goal of this work is to define mechanisms through which H. pylori cag PAI-positive strains induce gastric cancer. Recent studies in our laboratory have revealed an important role of salt in regulating CagA expression and in modulating the ability of H. pylori to cause aberrant epithelial cell responses. These findings, in conjunction with extensive literature indicating a role of dietary salt in gastric cancer, have led us to propose experiments that investigate the mechanism by which salt modulates CagA expression, investigate effects of salt on H. py/ori-induced cell signaling in vitro, and investigate effects of salt on H. py/on-induced disease progression in vivo.
Aim 1 proposes to analyze the regulatory mechanisms through which salt regulates expression of CagA. We will use multiple experimental approaches, including introduction of genetic mutations into H. pylori, isolation of DNA-protein complexes, and mass spectrometry analysis of such complexes.
Aim 2 will investigate alterations in gastric epithelial cells that occur in response to H. pylori strains that express mutant forms of CagA. Phenotypes selected for analysis will include translocation of CagA into host cells, induction of IL-8 secretion, (3-catenin activation and EGFR transactivation (in collaboration with Drs. Peek and Polk, respectively), and apoptosis, since each of these phenotypes is relevant to the pathogenesis of gastric cancer.
Aim 3 will extend these in vitro results into rodent models of H. py/or/-induced cancer that have been developed by Dr. Peek, including INS-GAS mice and Mongolian gerbils. These studies should lead to important advances in our understanding of the molecular mechanisms by which H. pylori modulates signaling in gastric epithelial cells and stimulates the development of gastric cancer. Ultimately, these studies should lead to advances in the prevention and therapy of malignancies that develop in the setting of chronic inflammation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA116087-05
Application #
8413059
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
2013-01-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$210,707
Indirect Cost
$72,764
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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

Showing the most recent 10 out of 189 publications