Autophagy; Cell Biology; Digestive System Diseases; Gastrointestinal Diseases; Pancreatic Diseases; Pancreatitis; 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 activation of digestive enzymes in the pancreatic acinar cell 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 the plasma protein, renalase, on reducing injury in pancreatitis (with Dr. Gary Desir and Loren Laine)
2) Effects of cigarette smoke toxins in cellular and animal models of pancreatitis
Activation of soluble adenylyl cyclase protects against secretagogue stimulated zymogen activation in rat pancreaic acinar cells.
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
Low extracellular pH modulates calcium signaling in the pancreatic acinar cell.
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
Reducing Extracellular pH Sensitizes the Acinar Cell to Secretagogue-Induced Pancreatitis Responses in Rats.
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
Vacuolar ATPase regulates zymogen activation in pancreatic acini.
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.
Regulation of zymogen processing in acinar cells by the ryanodine receptor.
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
Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity.
Hoque R, Farooq A, Ghani A, Gorelick F, Mehal WZ. Gastroenterology. 2014 Jun;146(7):1763-74.
Low pH enhances connexin32 degradation in the pancreatic acinar cell
Reed AM, Kolodecik T, Husain SZ, Gorelick FS.Am J Physiol Gastrointest Liver Physiol. 2014 Jul 1;307(1):G24-32
Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and Human Pancreatic Acinar Cells
Messenger SW, Thomas DD, Cooley MM, Jones EK, Falkowski MA, August BK, Fernandez LA, Gorelick FS, Groblewski GE. Cell Mol Gastroenterol Hepatol. 2015 Nov 1;1(6):695-709
Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer
Guo X, Hollander L, MacPherson D, Wang L, Velazquez H, Chang J, Safirstein R, Cha C, Gorelick F, Desir GV. Sci Rep. 2016 Mar 14;6:22996.