The Gastric Biology of Helicobacter Pylori

Summary

Principal Investigator: G Sachs
Affiliation: University of California
Country: USA
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

Top Publications

  1. pmc Analysis of the gastric H,K ATPase for ion pathways and inhibitor binding sites
    Keith Munson
    Laboratory of Membrane Biology, David Geffen School of Medicine at UCLA, and VA GLAHS, Los Angeles, California 90073, USA
    Biochemistry 46:5398-417. 2007
  2. doi Gastric H+,K+-ATPase
    Jai 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
  3. pmc The role of ExbD in periplasmic pH homeostasis in Helicobacter pylori
    Elizabeth A Marcus
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Helicobacter 18:363-72. 2013
  4. pmc The effects of varying acidity on Helicobacter pylori growth and the bactericidal efficacy of ampicillin
    E A Marcus
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90073, USA
    Aliment Pharmacol Ther 36:972-9. 2012
  5. pmc Differential distribution of ghrelin-O-acyltransferase (GOAT) immunoreactive cells in the mouse and rat gastric oxyntic mucosa
    Andreas Stengel
    Center for Neurobiology of Stress, CURE Digestive Diseases Research Center, USA
    Biochem Biophys Res Commun 392:67-71. 2010
  6. pmc Pharmacology of proton pump inhibitors
    Jai 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
  7. pmc Helicobacter pylori impedes acid-induced tightening of gastric epithelial junctions
    Elizabeth 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
  8. pmc Simple diagnostic tests to detect toxic alcohol intoxications
    Jai 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
  9. pmc The gastric H,K ATPase as a drug target: past, present, and future
    George Sachs
    Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
    J Clin Gastroenterol 41:S226-42. 2007
  10. pmc Molecular mechanisms in therapy of acid-related diseases
    J 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

Scientific Experts

  • Jai Moo Shin
  • Olga Vagin
  • G Sachs
  • Y Wen
  • D R Scott
  • Elizabeth A Marcus
  • E A Marcus
  • M Goebel
  • Andreas Stengel
  • Keith Munson
  • Elmira Tokhtaeva
  • N Inatomi
  • G T Nagami
  • N W G Lambrecht
  • A Stengel
  • Lixin Wang
  • YVETTE TACHE
  • Miriam Goebel
  • Nils W G Lambrecht
  • Richard J Law

Detail Information

Publications20

  1. pmc Analysis of the gastric H,K ATPase for ion pathways and inhibitor binding sites
    Keith Munson
    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]...
  2. doi Gastric H+,K+-ATPase
    Jai 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
    ....
  3. pmc The role of ExbD in periplasmic pH homeostasis in Helicobacter pylori
    Elizabeth A Marcus
    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...
  4. pmc The effects of varying acidity on Helicobacter pylori growth and the bactericidal efficacy of ampicillin
    E A Marcus
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90073, USA
    Aliment Pharmacol Ther 36:972-9. 2012
    ..Identifying growth responses to varying medium pH may allow design of more effective treatment regimens...
  5. pmc Differential distribution of ghrelin-O-acyltransferase (GOAT) immunoreactive cells in the mouse and rat gastric oxyntic mucosa
    Andreas Stengel
    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...
  6. pmc Pharmacology of proton pump inhibitors
    Jai 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...
  7. pmc Helicobacter pylori impedes acid-induced tightening of gastric epithelial junctions
    Elizabeth 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...
  8. pmc Simple diagnostic tests to detect toxic alcohol intoxications
    Jai 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...
  9. pmc The gastric H,K ATPase as a drug target: past, present, and future
    George 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...
  10. pmc Molecular mechanisms in therapy of acid-related diseases
    J 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...
  11. pmc The gastric HK-ATPase: structure, function, and inhibition
    Jai 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...
  12. pmc Inverse correlation between the extent of N-glycan branching and intercellular adhesion in epithelia. Contribution of the Na,K-ATPase beta1 subunit
    Olga 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...
  13. pmc Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438)
    Jai Moo Shin
    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...
  14. pmc Selective gene expression by rat gastric corpus epithelium
    M Goebel
    Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
    Physiol Genomics 43:237-54. 2011
    ....
  15. pmc A cis-encoded antisense small RNA regulated by the HP0165-HP0166 two-component system controls expression of ureB in Helicobacter pylori
    Yi 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...
  16. pmc Novel approaches to inhibition of gastric acid secretion
    George 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...
  17. pmc 1-Arylsulfonyl-2-(pyridylmethylsulfinyl) benzimidazoles as new proton pump inhibitor prodrugs
    Jai 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...
  18. pmc 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 pylori
    David 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...
  19. pmc Role of N-glycosylation in trafficking of apical membrane proteins in epithelia
    Olga Vagin
    Department of Physiology, David Geffen School of Medicine at University of California, Bldg 113, Rm 324, 11301 Wilshire Blvd, Los Angeles, California 90073, USA
    Am J Physiol Renal Physiol 296:F459-69. 2009
    ..Finally, we review existing hypotheses on the mechanism of apical sorting and discuss the potential roles of the lectins, VIP36 and galectin-3, as putative apical sorting receptors...