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.
|Raghunathan, Krishnan; Foegeding, Nora J; Campbell, Anne M et al. (2018) Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA. Infect Immun 86:|
|Scoville, Elizabeth A; Allaman, Margaret M; Brown, Caroline T et al. (2018) Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 14:|
|Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G et al. (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67:1247-1260|
|Blosse, Alice; Lehours, Philippe; Wilson, Keith T et al. (2018) Helicobacter: Inflammation, immunology, and vaccines. Helicobacter 23 Suppl 1:e12517|
|Coburn, Lori A; Singh, Kshipra; Asim, Mohammad et al. (2018) Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis. Oncogene :|
|Loh, John T; Beckett, Amber C; Scholz, Matthew B et al. (2018) High-Salt Conditions Alter Transcription of Helicobacter pylori Genes Encoding Outer Membrane Proteins. Infect Immun 86:|
|Noto, Jennifer M; Chopra, Abha; Loh, John T et al. (2018) Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 67:1793-1804|
|Butt, Julia; Blot, William J; Teras, Lauren R et al. (2018) Antibody Responses to Streptococcus Gallolyticus Subspecies Gallolyticus Proteins in a Large Prospective Colorectal Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 27:1186-1194|
|Shen, Xi; Liu, Liping; Peek, Richard M et al. (2018) Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes. Mucosal Immunol 11:1316-1328|
|Mera, Robertino M; Bravo, Luis E; Camargo, M Constanza et al. (2018) Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67:1239-1246|
Showing the most recent 10 out of 203 publications