Gastric acid secretion is a major factor in causation of GERD and peptic ulcer disease. H. pylori modifies secretion of gastrin and somatostatin and is also a major contributor to ulcerogenesis. Understanding of the pathways involved in stimulation of parietal and peptic cell function is important in defining the pathogenesis of ulcer disease. Studies of regulation of secretion have used various models. Intact animal studies have defined some neural pathways and endocrine and paracrine effectors. These models cannot usually define the cells directly involved in changes of gastric acid secretion. Isolated cell models have in general confirmed what has been found in animal models, but without high purity or video imaging the contribution of cell specific receptors and signaling has not been possible. To date, we have used video-imaging of calcium signals coupled with studies of histamine release to define receptors on the ECL cells at 85 percent purity and also shown Cai responses of individual G and D cells to ligands such as aromatic amino acids. With our recent (3 months) acquisition of a Zeiss confocal microscope, we now propose to continue these studies on isolated cells and now mainly to investigate more integrated models of gastric function, using isolated superfused fundic glands and segments of fundic epithelium, isolated perfused and superfused antral glands and antral segments. The responses of the individual cells in these models, i.e. ECL and fundic D cells, parietal and peptic cells for fundic models and G and D and peptic cells for antral models will enable studies of stimulation-secretion coupling as applied to endocrine-secretory cell coupling for the first time by direct visualization using appropriate dyes for Ca (mag-fluo-4) and pH (carboxy-SNARF-1) and acid secretion (acridine orange and 9-amino acridine). From this approach, the pathways involved with effects of PACAP, carbachol, CCK-8 and gastrin as possible neural or endocrine mediators of secretory stimulation and somatostatin, galanin, secretin and PYY as possible paracrine, neural or endocrine mediators of secretory inhibition will be determined. Preliminary confocal data, some of which are displayed in this application, show that this approach is technically feasible and conceptually rewarding. Hence this approach will provide additional insights into mechanisms of regulation of gastric secretion and enable illuminated interpretation of the pathophysiology of peptic ulcer disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046917-09
Application #
6635007
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
1994-05-01
Project End
2006-08-31
Budget Start
2003-05-01
Budget End
2006-08-31
Support Year
9
Fiscal Year
2003
Total Cost
$152,696
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Sachs, G; Marcus, E A; Wen, Y et al. (2018) Editorial: control of acid secretion. Aliment Pharmacol Ther 48:682-683
Wen, Yi; Scott, David R; Vagin, Olga et al. (2018) Measurement of Internal pH in Helicobacter pylori by Using Green Fluorescent Protein Fluorimetry. J Bacteriol 200:
Wen, Yi; Feng, Jing; Sachs, George (2013) Helicobacter pylori 5'ureB-sRNA, a cis-encoded antisense small RNA, negatively regulates ureAB expression by transcription termination. J Bacteriol 195:444-52
Wen, Yi; Feng, Jing; Scott, David R et al. (2011) A cis-encoded antisense small RNA regulated by the HP0165-HP0166 two-component system controls expression of ureB in Helicobacter pylori. J Bacteriol 193:40-51
Wen, Yi; Feng, Jing; Scott, David R et al. (2009) The pH-responsive regulon of HP0244 (FlgS), the cytoplasmic histidine kinase of Helicobacter pylori. J Bacteriol 191:449-60
Vagin, Olga; Tokhtaeva, Elmira; Yakubov, Iskandar et al. (2008) Inverse correlation between the extent of N-glycan branching and intercellular adhesion in epithelia. Contribution of the Na,K-ATPase beta1 subunit. J Biol Chem 283:2192-202
Sachs, George; Shin, Jai Moo; Vagin, Olga et al. (2007) The gastric H,K ATPase as a drug target: past, present, and future. J Clin Gastroenterol 41 Suppl 2:S226-42
Munson, Keith; Law, Richard J; Sachs, George (2007) Analysis of the gastric H,K ATPase for ion pathways and inhibitor binding sites. Biochemistry 46:5398-417
Wen, Yi; Feng, Jing; Scott, David R et al. (2007) The HP0165-HP0166 two-component system (ArsRS) regulates acid-induced expression of HP1186 alpha-carbonic anhydrase in Helicobacter pylori by activating the pH-dependent promoter. J Bacteriol 189:2426-34
Zer, Cindy; Sachs, George; Shin, Jai Moo (2007) Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factor-alpha signaling. Physiol Genomics 31:343-51

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