This is an application to investigate the control of exocrine pancreatic function at the cellular and molecular level. It includes support for five projects and three core facilities. The first project on calcium and stimulus secretion coupling in pancreatic acinar cells (PI:J.A. Williams) is concerned with the steps by which acetylcholine acts on muscarinic receptors to mobilize cellular calcium as well as the mechanism by which the rise in cytoplasmic calcium leads to changes in protein phosphorylation and secretion of digestive enzymes. The second project on the regulation of pancreatic cells by insulin and islet hormone is concerned with the physiological regulation of exocrine function by islet hormones including insulin, glucagon, somatostatin and pancreatic polypeptide. It also studies the cellular mechanism of insulin action on acinar cells. The third project on the characterization of receptors for cholecystokinin on acinar cells is concerned with the isolation and characterization of CCK receptors, the long term regulation of CCK receptors and biological responses, and the use of pancreatic acini for a bioassay of CCK in plasma. The fourth project on hormonal regulation of pancreatic gene expression will analyze the expression of pancreas specific exocrine genes as well as specific membrane antigens. The fifth project on control of pancreatic fluid secretion will use isolated acinar and duct cells as well as reconstituted cellular monolayers to study the mechanism of secretion of pancreatic juice and its regulation by hormones and neurotransmitters. The support requested is for fundamental research, but the resultant knowledge will be relevant to the understanding of pancreatic diseases including cystic fibrosis, pancreatitus and cancer.
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