The Gastric Biology of Helicobacter Pylori
Principal Investigator: G Sachs
Affiliation: University of California
Abstract: DESCRIPTION (provided by applicant): The aims are to investigate the gastric physiology of the gastric pathogen Helicobacter pylori. Specific Aims: (A). Identify the acid response regulon and signaling system of the cytoplasmic pH sensor. HP0244 is a previously unsuspected sensor of cytoplasmic pH. Using transcriptome analysis after pH 2.5 incubation, the HP0244, HP0703 independent, regulon will be identified to separate periplasmic (HP0165) from cytoplasmic pH) regulation and confirmed by qPCR;(B) Identify colonization dependent gene expression and evaluate pH control of their expression by comparative transcriptome analysis of H. pylori from infected gerbils with and without acid suppression. Transcriptome analysis of H. pylori infecting the gerbil stomach compared to in vitro cultured H. pylori showed a greater up-regulation of genes encoding proteins involved in acid acclimation than at pH 4.5 in vitro, likely reflecting a pH <4.5 in the niche of the colonizing organisms. Cell division, wall and protein biosynthesis genes were also increased. Preliminary data show that acid inhibition by a PPI reduces expression of the former group to the level found at pH 4.5 in vitro but augments expression of the latter three groups of growth-related genes, this may explain the need for a combination of a PPI with growth-dependent antibiotics for triple therapy. These data may lead to dual therapy with a long acting PPI + amoxicillin;(C) Investigate pH-induced activation and trafficking of a urease complex and other proteins to UreI on the inner membrane and determine whether this is regulated by HP0165 or HP0244 The expression of urease by H. pylori (~10% of total protein) is essential for gastric infections. However, at neutral pH, only 1/3rd of urease is active, 2/3rd is present as inactive apoenzyme. pH-dependent activation of the apoenzyme would provide a more rapid response to acid than de novo synthesis. Preliminary results suggest that there is activation and translocation of urease at acidic pH that is dependent on HP0165. UreI serves as the membrane anchor for the pH- dependent relocation of urease to the inner membrane and this is required for activation of apourease. This research may provide new leads for improvement eradication therapy thereby decreasing the risk of peptic ulcer disease and gastric cancer. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is responsible for peptic ulcers and a fortyfold increased risk of gastric cancer. We shall analyze the physiology of H. pylori in the stomach by investigating signaling systems for genes regulated by gastric pH and the role of urease trafficking and activation in infection. A better understanding of effects of acid inhibition on H. pylori may allow improvement or replacement of triple therapy for eradication.
Funding Period: ----------------1997 - ---------------2013-
more information: NIH RePORT
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Laboratory of Membrane Biology, David Geffen School of Medicine at UCLA, and VA GLAHS, Los Angeles, California 90073, USA
Biochemistry 46:5398-417. 2007..Finally, the expanded luminal vestibule of the E2P model explains high-affinity ouabain binding in a mutant of the H,K ATPase [Qiu et al. (2005) J. Biol. Chem. 280, 32349-32355]...
- Gastric H+,K+-ATPaseJai Moo Shin
Department of Physiology and Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
Compr Physiol 1:2141-53. 2011....
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Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Helicobacter 18:363-72. 2013..The ExbB/ExbD/TonB complex transfers energy from the inner to outer membrane, providing the driving force for nickel uptake. Therefore, the aim of this study was to determine the contribution of ExbD to pH homeostasis...
- The effects of varying acidity on Helicobacter pylori growth and the bactericidal efficacy of ampicillinE A Marcus
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90073, USA
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Center for Neurobiology of Stress, CURE Digestive Diseases Research Center, USA
Biochem Biophys Res Commun 392:67-71. 2010..Detection of GOAT in the plasma raises the possibility that ghrelin octanoylation may occur in the circulation and the fasting-induced increase in GOAT may contribute to the increase of acylated ghrelin after fasting...
- Pharmacology of proton pump inhibitorsJai Moo Shin
Membrane Biology, David Geffen School of Medicine, University of California at Los Angeles, Room 324, Building 113, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
Curr Gastroenterol Rep 10:528-34. 2008..PPIs with longer half-life promise to improve acid suppression. All PPIs give excellent healing of peptic ulcers and produce good results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori...
- Helicobacter pylori impedes acid-induced tightening of gastric epithelial junctionsElizabeth A Marcus
DGSOM at UCLA, VA GLAHS, 11301 Wilshire Blvd, Bldg 113, Rm 324, Los Angeles, CA 90073
Am J Physiol Gastrointest Liver Physiol 305:G731-9. 2013..H. pylori diminishes acid-induced tightening of cell junctions in a urease-dependent manner, suggesting that local pH elevation promotes barrier compromise and progression to mucosal damage...
- Simple diagnostic tests to detect toxic alcohol intoxicationsJai Moo Shin
Medical and Research Services VHAGLA Healthcare System, UCLA Membrane Biology Laboratory, Division of Nephrology VHAGLA Healthcare System and David Geffen School of Medicine, Los Angeles, CA, USA
Transl Res 152:194-201. 2008..The relatively high sensitivity and specificity of the tests as a whole will facilitate the rapid diagnosis of each of these alcohol intoxications...
- The gastric H,K ATPase as a drug target: past, present, and futureGeorge Sachs
Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
J Clin Gastroenterol 41:S226-42. 2007..The review concludes with a discussion of the mechanism of action and binding regions of a possible new class of drug for acid control, the K competitive acid pump antagonists...
- Molecular mechanisms in therapy of acid-related diseasesJ M Shin
Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
Cell Mol Life Sci 65:264-81. 2008..Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists...
- The gastric HK-ATPase: structure, function, and inhibitionJai Moo Shin
Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
Pflugers Arch 457:609-22. 2009..This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases...
- Inverse correlation between the extent of N-glycan branching and intercellular adhesion in epithelia. Contribution of the Na,K-ATPase beta1 subunitOlga Vagin
Department of Physiology, School of Medicine, University of California, Los Angeles, Veterans Administration Greater Los Angeles Health Care System, Los Angeles, California 90073, USA
J Biol Chem 283:2192-202. 2008..These results suggest epithelial cells can regulate tightness of cell junctions via remodeling of N-glycans, including those linked to the Na,K-ATPase beta(1)-subunit...
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Department of Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, 11301 Wilshire Blvd, Bldg 113, CA 90073, USA
J Pharmacol Exp Ther 339:412-20. 2011..Hence, this K(+)-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class...
- Selective gene expression by rat gastric corpus epitheliumM Goebel
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
Physiol Genomics 43:237-54. 2011....
- A cis-encoded antisense small RNA regulated by the HP0165-HP0166 two-component system controls expression of ureB in Helicobacter pyloriYi Wen
The Membrane Biology Laboratory, Department of Physiology, David Geffen School of Medicine at UCLA, 11301 Wilshire Blvd, Bldg 113, Rm 324, Los Angeles, CA 90073, USA
J Bacteriol 193:40-51. 2011..The ability of the HP0165-HP0166 TCS to both increase and decrease ureB expression at low and high pHs, respectively, facilitates gastric habitation and colonization over the wide range of intragastric pHs experienced by the organism...
- Novel approaches to inhibition of gastric acid secretionGeorge Sachs
Department of Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
Curr Gastroenterol Rep 12:437-47. 2010..pylori eradication...
- 1-Arylsulfonyl-2-(pyridylmethylsulfinyl) benzimidazoles as new proton pump inhibitor prodrugsJai Moo Shin
Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
Molecules 14:5247-80. 2009..New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition...
- Cytoplasmic histidine kinase (HP0244)-regulated assembly of urease with UreI, a channel for urea and its metabolites, CO2, NH3, and NH4(+), is necessary for acid survival of Helicobacter pyloriDavid R Scott
Department of Physiology, David Geffen School of Medicine at UCLA, 405 Hilgard Ave, Los Angeles, California 90024, USA
J Bacteriol 192:94-103. 2010..Assembly of a pH-regulatory complex of active urease with UreI provides an advantage for periplasmic buffering...
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Department of Physiology, David Geffen School of Medicine at University of California, Bldg 113, Rm 324, 11301 Wilshire Blvd, Los Angeles, California 90073, USA
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