Fred S. Gorelick, M.D.

Professor of Internal Medicine/Section of Digestive Diseases, and Cell Biology We examine the mechanisms that initiate pancreatitis which begins with the premature activation of pancreatic digestive enzymes and have found that activation takes place in an organelle that has features of both a lysosome and classic secretory vesicle
Phone: (203) 932-5711 x3679 Lab: (203) 932-5711 x3680/3678 Fax: (203) 937-3852 e-mail: fred.gorelick@yale.edu		Section of Digestive Diseases Department of Internal Medicine Yale University School of Medicine 333 Cedar Street PO Box 208019 New Haven, CT 06520-8019 <Courier Address> GI Research Laboratory Building 27 VA Health Care Connecticut 950 Campbell Avenue West Haven, CT 06510

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Our laboratory studies the cell biology of several processes that are related to organ physiology and disease.

We are primarily interested in mechanisms within the acinar cell that initiate pancreatitis, a severe inflammatory condition of the pancreas. An initiating event in acute pancreatitis is the premature activation of pancreatic proteases within the acinar cell. Normally, these only become active after reaching the small intestine. We are interested in the compartment in which activation occurs and the molecular mechanisms of the activation. Distinct patterns of calcium signaing and activation of a vacuolar ATPase appear to be required for this protease activation. We use intact cells and a cell-free system to study the biology of this event.

Figure 1. Premature proteolytic activation of pancreatic digestive enzymes is an initiating step in acute pancreatitis.  As indicated the arrow in the cartoon, this activation takes place in a secretory compartment of unknown identity.  Shown in the lower micrographs is labeling of the trypsinogen activation peptide, a marker of trypsin activation.

We are also interested in the regulation of intracellular trafficking and have previous characterized Sec31, a member of the COPII coat.  Our recent studies have examined the biogenesis of lipid-carrying vesicles (chylomicrons) in small intestinal cells that mediate transport between the endoplasmic reticulum and Golgi complex.

Figure 2. Regulation of budding from the endoplasmic reticulum (ER).  a) The COPII coat is comprised of multiple proteins that undergo ordered addition to form a coat. b) Overlap in the labeling of Sec31 and GFP Sec13. c) Overlap in the COPII protein Sec23 and the chylomicron protein ApoB48 in intestinal epithelial cells.  D) Cartoon comparing budding of vesicles containing nascent proteins and lipids (PCTV)

Selected Publications

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Siddiqi SA, Gorelick FS, Mahan JT, and Mansbach CM II. (2003)   COPII proteins are required for Golgi fusion but not for endoplasmic reticulum budding of the pre-chylomicron transport vesicle. J Cell Sci. 116: 415-427.  

Lu Z, Kolodecik TR, Karne S, Nyce M, and Gorelick FS. (2003)  Effect of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini. Am J Physiol Gastrointest Liver Physiol. 285: G822-828.  

Waterford SD, Kolodecik TR, Thrower EC, Gorelick FS. (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 

E. Thrower A. Devilla-Villa, T. Kolodecik and F. Gorelick. Zymogen activation in a reconstituted pancreatic acinar cell system. Am J Physiol Gastrointest Liver Physiol. 2006 290(5):G894-9

Cai D, Netzer WJ, Zhong M, Lin Y, Du G, Frohman M, Foster DA, Sisodia SS, Xu H, Gorelick FS, Greengard P. Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. Proc Natl Acad Sci U S A. 2006 103:1941-6

Chaudhuri A, Husain SZ, Kolodecik TR, Grant WM, Gorelick F. Cyclic AMP-dependent protein kinase and Epac mediate cyclic AMP responses in pancreatic acini.
Am J Physiol Gastrointest Liver Physiol. 2007 292: G1403-G1410