Cell Biology; Digestive System Diseases; Gastrointestinal Diseases; Pancreatic Diseases; Pancreatitis; Protein Kinase C; Pancreas, Exocrine; AMP-Activated Protein Kinases; Proteolysis
The central interest of our laboratory is the mechanisms that initiate pancreatitis, a severe inflammatory disease that causes death in up to 5% of patients. The disease begins with the premature activation of pancreatic digestive enzymes within the acinar cell, inhibition of secretion, activation of inflammatory pathways, and cell death. We study the pathways that initiate disease with a goal of identifying therapeutic targets.
Speciailzed Terms: Exocrine pancreas; Pancreatitis; Intracellular proteolysis; Vacuolar ATPase; AMPK; Protein kinase C
Extensive Research Description
We have found that this activation takes place in a special cellular organelle that has features of both a lysosome and classic secretory vesicle. We are characterizing this novel compartment and the second messenger signals that stimulate zymogen activation and are focusing on the role of vacuolar-ATPases (vATPase) and organelle acidification. vATPase are distinctive proton transporters that are dynamically regulated by assembly and disassembly of membrane-bound and soluble subunits.
We have found that distinct protein kinases, such as AMPK, regulate the activation and inactivation of the vATPase. These studies have direct clinical implications. Thus, we have recently found that an acute acid load worsens pancreatitis responses in an animal model of this disease. Further, certain metabolic products, such as lactate may lessen the severity of disease. Finally, pharmacological agents that enhance the activity of AMPK may be useful for disease treatment and/or prevention. We plan to pursue these studies using rodents models of pancreatitis, human acinar cells, and to collobrate with clinical investigators to examine these pathways in patients.
1) Effects of AMPK activators, especially salicylate, in cellular and animal models of acute pancreatitis
2) Effects of cigarette smoke toxins in cellular and animal models of pancreatitis (with Dr. Edwin Thrower)
3) Effects of lactate in cellular and animal models of pancreatitis (with Dr. Rafaz Hoque and Waj Mehal)
- Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation. Shugrue CA, Alexandre M, Diaz de Villalvilla A, Kolodecik TR, Young LH, Gorelick FS, Thrower EC. (2012) Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation.
- Activation of soluble adenylyl cyclase protects against secretagogue stimulated zymogen activation in rat pancreaic acinar cells. Kolodecik TR, Shugrue CA, Thrower EC, Levin LR, Buck J, Gorelick FS. PLoS One. 2012;7(7):e41320
- Reed AM, Husain SZ, Thrower E, Alexandre M, Shah A, Gorelick FS, Nathanson MH. Low extracellular pH modulates calcium signaling in the pancreatic acinar cell. J. Biological Chemistry 2011 286(3):1919-26 PMC330423
- Bhoomagoud M, Jung T, Atladottir J, Kolodecik TR, Shugrue C, Chaudhuri A, Thrower EC, Gorelick FS Reducing Extracellular pH Sensitizes the Acinar Cell to Secretagogue-Induced Pancreatitis Responses in Rats. Gastroenterology. 137: 1083-1092, 2009
- Waterford, S., Kolodecik, T., Thrower, E., and Gorelick, F. (2005). Vacuolar ATPase regulates zymogen activation in pancreatic acini. J. Biol. Chem. 280(7):5430-4.
- S. Husain, T. Kolodecik, M. Nathanson, F. Gorelick. Regulation of zymogen processing in acinar cells by the ryanodine receptor. Proc Natl Acad Sci, USA. 2005 102:14386-91