• Korc, Murray (PI)

Project: Research project

Project Details


The acinar cell of the exocrine pancreas synthesizes a large number of
digestive enzymes that are secreted into the gastrointestinal tract. Both
hormonal and dietary factors have been implicated in the regulation of the
synthesis of these enzymes. However, the mechanisms whereby this
regulation is effected are not known. Further, it is not clear whether
regulation of pancreatic enzyme synthesis and secretion are linked via
intracellular feedback mechanisms, coupled to respond to the sme stimuli,
or independently regulated. We have recently determined that manganese
exerts direct effects on pancreatic enzyme secretion and protein synthesis,
enhancing synthesis at low concentrations, and inhibiting synthesis at
higher concentrations. We have previously shown that cholecystokinin and
carbachol, two pancreatic secretagogues that are known to act via Ca++,
also exert biphasic effects on pancreatic protein synthesis. Our
preliminary findings indicate that the actions of manganese on protein
synthesis, like the actions of cholecystokinin and carbachol, are modulated
by Ca++. Inasmuch as the exocrine pancreas is rich in manganese, these
observations suggest that manganese may act as an intracellular mediator
that coordinates the regulation of pancreatic protein synthesis with enzyme
secretion. Because 95% of protein synthesis in the pancreas is directed
toward the production of exportable digestive enzymes, manganese may thus
participate in the regulation of pancreatic enzyme synthesis. To determine
the mechanism of action of manganese, we will study its uptake,
intracellular localization, effects on Ca++ fluxes, and actions on protein
phosphorylation. We will use both short-term preparations of isolated
pancreatic acini and long-term cultures of acinar cells. To determine
whether there are any interactions between pancreatic secretagogues and
manganese, the effects of manganese on these functions will be correlated
with the effects of cholecystokinin and vasoactive intestinal polypeptide.
The biological significance of these in vitro effects of manganese will be
investigated by inducing dietary manganese deficiency in rats, and
subsequently in other animal species. We will study the pancreatic
ultra-structure, enzyme content and synthesis, and responsiveness to
pancreatic secretagogues in pancreatic tissues isolated from
manganese-deficient animals. Finally, we will determine whether the
pancreas of these animals has the capacity to adapt to dietary alterations.
Effective start/end date4/1/843/30/87


  • National Institutes of Health


  • Medicine(all)

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