The goal of this study is to define the molecular mechanisms underlying the hypochlorhydria associated with Helicobacter pylori-induced gastritis. Clinical and in vitro evidence associates gastric corpus H. pylori infection with acid hyposecretion and generation of an inflammatory response. In a significant subset of patients, the ensuing gastritis progresses to atrophic gastritis, intestinal metaplasia, dysplasia, and eventually gastric adenocarcinoma. This study tests the hypothesis that acute H. pylori infection down-regulates H,K-ATPase (proton pump) gene expression by perturbing normal interactions of cis-regulatory elements on the HKalpha gene promoter and cellular trans-activating proteins, thereby inhibiting parietal cell acid secretion. In preliminary studies, exogenous H,K-ATPase alpha subunit (HKalpha) promoter sequences transiently transfected into human gastric adenocarcinoma (AGS) cells were responsive to acid secretory agonists and antagonists, and were inhibited by H. pylori infection. This approach forms the experimental basis for three Specific Aims: 1) To identify in gastric epithelial cells H. pylori-responsive c/s-regulatory elements and cognate transcription factors involved in regulation of HK( gene transcription; 2) To investigate the mechanisms whereby specific H. pylori genotypes induce down-regulation of HKalpha gene transcription; and 3) To investigate HKalpha subunit gene transcription and translation within H. pylori.infected and uninfected human gastric mucosa. Basal and H. pylori-responsive cis-regulatory elements and transactivating proteins in transfected ACTS cells will be investigated by deletion analysis, electrophoretic mobility shift, supershift, and solid-phase protein/DNA interaction assays. Acid-inhibitory H. pylori genotypes will be identified by assessing HKa promoter activity in transfected ACTS cells infected with H. pylori mutant strains deficient in virulence-associated genes. Finally, gastric H,K-ATPase mRNA levels and proton pump expression, as measured by real-time RT-PCR and quantitative immunochemistry in a large, well documented archive of human gastric biopsies, will be investigated in the context of intragastric pH, infection status, H. pylori strain identity, and anatomic site of infection. These studies will establish the mechanistic basis of H. pylori-induced gastric hypochlorhydria, and add to the understanding of H. pylori pathophysiology.
| Hammond, Charles E; Beeson, Craig; Suarez, Giovanni et al. (2015) Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion. Am J Physiol Gastrointest Liver Physiol 309:G193-201 |
| Zhang, Yong-Mei; Noto, Jennifer M; Hammond, Charles E et al. (2014) Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase ?-subunit gene expression by miRNA. Am J Physiol Gastrointest Liver Physiol 306:G606-13 |
| Smolka, Adam J; Backert, Steffen (2012) How Helicobacter pylori infection controls gastric acid secretion. J Gastroenterol 47:609-18 |
| Tegtmeyer, Nicole; Wessler, Silja; Backert, Steffen (2011) Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J 278:1190-202 |
| Saha, Arindam; Backert, Steffen; Hammond, Charles E et al. (2010) Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology 139:239-48 |
| Saha, Arindam; Hammond, Charles E; Beeson, Craig et al. (2010) Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa. Gut 59:874-81 |
| Saha, Arindam; Hammond, Charles E; Gooz, Monika et al. (2008) The role of Sp1 in IL-1beta and H. pylori-mediated regulation of H,K-ATPase gene transcription. Am J Physiol Gastrointest Liver Physiol 295:G977-86 |
| Saha, Arindam; Hammond, Charles E; Trojanowska, Maria et al. (2008) Helicobacter pylori-induced H,K-ATPase alpha-subunit gene repression is mediated by NF-kappaB p50 homodimer promoter binding. Am J Physiol Gastrointest Liver Physiol 294:G795-807 |
| Saha, Arindam; Hammond, Charles E; Gooz, Monika et al. (2007) IL-1beta modulation of H,K-ATPase alpha-subunit gene transcription in Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol 292:G1055-61 |
| Lapierre, Lynne A; Avant, Kenya M; Caldwell, Catherine M et al. (2007) Characterization of immunoisolated human gastric parietal cells tubulovesicles: identification of regulators of apical recycling. Am J Physiol Gastrointest Liver Physiol 292:G1249-62 |
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