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John Williams

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Primary Appointment: Molec & Integrative Physiology
Primary PIBS Dept.: Molecular and Integrative Physiology
Other PIBS Depts.: Bioinformatics
Department Website



 DESCRIPTION OF RESEARCH
  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 (whole animal) levels. Isolated primary cells from the pancreas of normal and transgenic animals, cell lines as well as mice fed different diets are being studied. Several main areas are being investigated. These include mechanisms of secretion of digestive enzymes by exocytosis, regulation of digestive enzyme synthesis, regulation of pancreatic growth, and abnormalities of function in experimental pancreatitis. In the area of secretion we are focused on proteins on the external surface of the zymogen granule, particularly Rabs and on the actin cytoskeleton. We are using a proteomics approach to identify all proteins present on the granules, their topology, and interactions. We are currently evaluating possible guanine nucleotide exchange factors for Rab3D, Rab27B and Rap1 using affinity chromatography and mass spectrometry to identify interacting proteins. We are using adenoviral vectors to express mutant small G-proteins and evaluate their effect on actin filament structure and secretion. These studies in addition to increasing understanding of acinar cell secretion will increase general understanding of hormone secretion.

In a 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 neurotransmitters, insulin and branched chain amino acids. The major intracellular regulatory pathway involves phosphoinositide 3 kinase, mTOR and S6 kinase. When demand for digestive enzymes is prolonged we have shown in rodents that the pancreas will grow through division of differentiated acinar cells and that this is mediated primarily by CCK. We have identified a central role for the calcium activated phosphatase, calcineurin and the mTOR pathway in regulating this growth. We are using gene chip analysis and quantitative PCR to evaluate changes in gene expression during growth and have identified NFATs and NFAT regulated genes as downstream targets for calcineurin. We also are studying growth regulation in primary cultures of acinar cells. These cultures model the dedifferentiation and growth that occurs during regeneration after acute pancreatitis. These processes in culture are mediated by JNK activation and the induction of c-jun and AP-1 transcription factor and also require the mTOR pathway but not calcineurin.