REGULATION OF GASTRIN SYNTHESIS AND RELEASE

  • Lichtenberger, Lenard M, (PI)

Project: Research projectResearch Project

Description

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.
StatusFinished
Effective start/end date4/1/786/30/90

Funding

  • National Institutes of Health
  • National Institutes of Health

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Gastrins
Amines
Gastrin-Secreting Cells
Carboxy-Lyases
Secretory Vesicles
Stomach
Peptide Initiation Factors
Pronase
Deoxyribonucleases
Gastric Acid
Monoamine Oxidase
Laboratory Animals
Enzymes
Radioimmunoassay
Digestion
Electron Microscopy
Healthy Volunteers
Flow Cytometry
Animal Models
Hormones

Keywords

  • Medicine(all)