Fred Gorelick MD
Professor of Medicine (Digestive Diseases) and of Cell Biology; Associate Director, Yale M.D., Ph.D. Program
Exocrine pancreas; pancreatitis; intracellular proteolysis; vacuolar ATPase; AMPK; protein kinase C
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.
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 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.
- Chung C, Mader CC, Schmitz JC, Atladottir J, Fitchev P, Cornwell ML, Koleske AJ, Crawford SE, Gorelick F. Vacuolar-ATPase modulates MMP activities and invasive properties in human pancreatic ductal adenocarcinoma (PDAC). In Press, Laboratory Investigation NIHMS257466
- Lugea A, Tischler D, Nguyen J, Gong J, Gukovsky I, French SW, Gorelick FS, Pandol SJ. Adaptive Unfolded Protein Response Attenuates Alcohol-induced Pancreatic Damage. Gastroenterology 2011 140(3):987-997. PMC3057335
- 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