The long term goals of this project are two-fold: 1) to identify the dietary factors required for the initiation of the postprandial release of gastrin in both laboratory animals and humans; and 2) to characterize the intracellular stimulus-secretion coupling mechanism within the G cells. It is our hope that information obtained from these studies will not only increase our understanding of physiological and molecular mechanism which regulates gastrin levels in normal subjects but provide insight into the genesis of hypergastrinemia in conditions associated with peptic ulcer disease. During the preceding project period we have obtained evidence that: 1) dietary amines may play a central role in the stimulation of meal-induced gastrin release; 2) dietary hydrophobic amino acids may trigger gastrin secretion by diffusing in the G cell and being converted by intracellular decarboxylase enzymes to stimulatory amines; and 3) certain pathological hypergastrinemic states may be caused by the accumulation of high concentrations of amines within the gastric lumen. In the studies outlined in this proposal we will attempt to define the molecular mechanisms by which amine concentration is regulated intracellularly (with a focus being placed on the roles of amine-generative, decarboxylase, and degenerative, monoamine oxidase, enzymes); and whether the accumulation of amines within the G cell is coupled to hormone secretion (with a focus being placed on the effect of amines on secretory granule pH). Conversely, we plan to investigate the importance of dietary amine trapping within the stomach at low luminal pH in the mechanism by which gastric acid inhibits the postprandial release of gastrin. In addition to these studies we plan to investigate the role of dietary amines in the postprandial release of gastrin in healthy human subjects and the contribution of gastric amine accumulation to the abnormal elevations in circulating gastrin levels induced in certain animal models and encountered in patients in Acute Renal Failure. The techniques to be employed in these studies include: 1) isolation of antral glandular cells by selective pronase/DNase digestion with an attempt to further purify the G cells by flow cytometry; 2) isolation of gastrin secretory granules by isosmotic gradient density centrifugation; 3) fluorescent morphometry; 4) electron microscopy and 5) radioimmunoassay.
| Dial, E J; Huang, J; Delansorne, R et al. (1986) Monoamine oxidase: an important intracellular regulator of gastrin release in the rat. Gastroenterology 90:1018-23 |
| Lichtenberger, L M; Nelson, A A; Graziani, L A (1986) Amine trapping: physical explanation for the inhibitory effect of gastric acidity on the postprandial release of gastrin. Studies on rats and dogs. Gastroenterology 90:1223-31 |
