Areas of Interest
Research in Dr Williams’ laboratory focuses on the regulation of pancreatic function by hormones and neurotransmitters and is carried out at the cellular, molecular and integrative levels. Isolated cells from the pancreas of normal and transgenic animals as well as cell lines are being used. Several main areas are being studied. These include mechanisms of secretion of digestive enzymes by exocytosis, regulation of digestive enzyme synthesis to match the need, regulation of pancreatic growth, and abnormalities of function in experimental pancreatitis. In the area of secretion we study the intracellular mechanism by which receptors for cholecystokinin (CCK) and acetylcholine trigger the release of digestive enzymes by exocytosis. Intracellular messengers, particularly Ca2+ are being studied by biochemical and imaging techniques. We have also identified several novel proteins undergoing regulatory phosphorylation changes in response to Ca 2+ signaling. To study the terminal steps in secretion, proteins of the zymogen granule membrane, including small GTP binding proteins are being identified by a proteomics approach using mass spectrometry and subsequently characterized for biological activity. We have identified the presence of the small G proteins Rab3D, Rab27B, and Rap1 on the zymogen granule and used adenoviral delivery of dominant negative mutants to show their importance in secretion. Both upstream regulatory and downstream effectors are now being searched for. In the second area of research we are studying processes that ensure an adequate supply of digestive enzymes. We are characterizing the regulated steps in the translational control of protein synthesis and have shown that fasting decreases and meal eating increases digestive enzyme synthesis at the translational level. Stimulatory factors include CCK, vagal neurotransmitter, insulin and branched chain amino acids. The major intracellular regulatory pathway involves mTOR and S6 kinase. When demand for digestive enzymes is prolonged we have shown in rodents that the pancreas will grow and that this is mediated primarily by CCK stimulation of mitogenesis. We have identified a central role for the calcium activated phosphatase, calcineurin in regulating this growth and are currently investigating the role of the ERK pathway. We have also found that the amount of protein in the diet affects the size of acinar cells without mitogenesis. We are using gene chip analysis and quantitative PCR to evaluate changes in gene expression during growth. Current work utilizes genetically modified mice to identify the importance of specific signal transduction pathways.
M.D., Ph.D. University of Washington, 1968