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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine A Subcommittee 2 (GMA)
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Hamilton, Frank A
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University of California Los Angeles
Schools of Medicine
Los Angeles
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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
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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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