Peptic ulcer disease remains a significant burden in the US healthcare system and worldwide, caused in large part by the presence of the gastric pathogen Helicobacter pylori or the upper GI toxicity of ingested therapeutic drugs. The rationale for our work is that improved or alternative therapeutic strategies can be based on understanding the mechanisms of gastric defense rallied against such challenges. Based on preliminary studies, we hypothesize that the juxtamucosal environment, including a role for both intracellular and extracellular Ca2+, is a central regulator of gastric repair of the surface epithelium. The objective of this application is to identify the underlying mechanisms for inhibited gastric epithelial repair in response to the GI- toxic bisphosphonate drugs, the H. pylori pathogen, or a combination of these stressors. We specifically ask if the pathogenesis from acute H. pylori and bisphosphonate drugs is via their interference with host Ca2+ signaling, which we show to be important for repair. We have pioneered optical technologies that allow real- time creation of focal damage and continual quantification of repair. Our work focusing on the repair of focal lesions in vivo will be extrapolated to experiments evaluating gastritis and ulceration to enhance relevance to gastric pathologies observed clinically. In this application, we introduce the novel ability to image intracellular calcium mobilization in vivo in the gastric surface epithelium, and extracellular calcium mobilization in the juxtamucosal microenvironment of the gastric lumen.
Our first aim i s to examine the role of calcium-dependent signaling during the repair of focal gastric lesions. Experiments are based on preliminary findings that show phospholipase C, protein kinase C, prostaglandins, and both intracellular and extracellular calcium mobilization are required for efficient gastric repair in the intact stomach. We will define the hierarchy and sequence among these calcium-dependent signaling routes that promote gastric repair and ask if the GI-toxic bisphosphonate drugs interfere with gastric epithelial repair by interrupting this Ca2+ signaling.
Our second aim examines how the presence of H. pylori affects gastric repair. Experiments are based on preliminary observations that fluorescently-labeled H. pylori accumulate specifically at the site of a focal lesion within minutes, and slow the repair of that lesion. We also observe selective accumulation of H. pylori at sites of macroscopic ulceration. We will ask if H. pylori accumulates at damage sites due to bacterial chemosensing, using H. pylori mutants defective in chemosensing genes and manipulating the level of potential chemoattractants in the juxtamucosal space. We will evaluate the impact of this accumulation on ulcer healing and on progression of bisphosphonate gastritis. The outcomes will provide a unique window into understanding early factors in pathogenesis, which have potential to lead to preventive interventions. Public Health Relevance: Gastritis and peptic ulcer disease are a significant burden in the US healthcare system, caused in large part by the presence of the stomach pathogen Helicobacter pylori or the toxicity of ingested therapeutic drugs (such as aspirin, or the bisphosphonate drugs used to treat osteoporosis). This project explores the cellular and molecular mechanisms underlying the stomach irritation caused by initial exposure to H. pylori or bisphosphonates, and the remarkable ability of the stomach to heal itself quickly in response to such insults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054940-14
Application #
8517098
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Carrington, Jill L
Project Start
1999-08-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
14
Fiscal Year
2013
Total Cost
$377,968
Indirect Cost
$137,224
Name
University of Cincinnati
Department
Physiology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Aihara, Eitaro; Montrose, Marshall H (2014) Importance of Ca(2+) in gastric epithelial restitution-new views revealed by real-time in vivo measurements. Curr Opin Pharmacol 19:76-83
Demitrack, Elise S; Aihara, Eitaro; Kenny, Susan et al. (2012) Inhibitors of acid secretion can benefit gastric wound repair independent of luminal pH effects on the site of damage. Gut 61:804-11
Xue, Lin; Aihara, Eitaro; Wang, Timothy C et al. (2011) Trefoil factor 2 requires Na/H exchanger 2 activity to enhance mouse gastric epithelial repair. J Biol Chem 286:38375-82
Xue, Lin; Aihara, Eitaro; Podolsky, Daniel K et al. (2010) In vivo action of trefoil factor 2 (TFF2) to speed gastric repair is independent of cyclooxygenase. Gut 59:1184-91
Demitrack, Elise S; Soleimani, Manoocher; Montrose, Marshall H (2010) Damage to the gastric epithelium activates cellular bicarbonate secretion via SLC26A9 Cl(-)/HCO(3)(-). Am J Physiol Gastrointest Liver Physiol 299:G255-64
Starodub, Olga T; Demitrack, Elise S; Baumgartner, Heidi K et al. (2008) Disruption of the Cox-1 gene slows repair of microscopic lesions in the mouse gastric epithelium. Am J Physiol Cell Physiol 294:C223-32
Gens, J Scott; Du, Hongwei; Tackett, Lixuan et al. (2007) Different ionic conditions prompt NHE2 and NHE3 translocation to the plasma membrane. Biochim Biophys Acta 1768:1023-35
Baumgartner, Heidi K; Montrose, Marshall H (2004) Regulated alkali secretion acts in tandem with unstirred layers to regulate mouse gastric surface pH. Gastroenterology 126:774-83
Baumgartner, H K; Starodub, O T; Joehl, J S et al. (2004) Cyclooxygenase 1 is required for pH control at the mouse gastric surface. Gut 53:1751-7
Hirokawa, Masahiko; Takeuchi, Tetsu; Chu, Sahaoyou et al. (2004) Cystic fibrosis gene mutation reduces epithelial cell acidification and injury in acid-perfused mouse duodenum. Gastroenterology 127:1162-73

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