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Professor of Internal Medicine/Section of Digestive Diseases, and Cell Biology |
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Phone: (203) 932-5711 x3679 Lab: (203) 932-5711 x3680/3678 Fax: (203) 937-3852 e-mail: fred.gorelick@yale.edu |
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Section of Digestive Diseases <Courier Address> |
First, the mechanisms residing within the acinar cell that initiate pancreatitis are studied in cellular models of the disease. Many forms of pancreatitis appear to begin 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. Further, we have developed a cell-free reconstitution system to examine the molecular regulation of this processing.
My second area of study examines the factors that regulate the movement of newly synthesized protein in gastrointestinal epithelial cells. Disordered protein movement is now recognized as a basis of a growing number of diseases including some forms of cystic fibrosis, hyperlipidemia, and alpha1-antitrypsin deficiency. Our laboratory identified the final member of the mammalian COPII complex, Sec31. This complex mediates vesicle movement from the endoplasmic reticulum (ER) to Golgi complex. We are studying the role of Sec31 isoforms in moving specific cargo between these compartments. In collaborative studies, we have begun to compare the regulation of vesicles that carry the bulk of nascent proteins vs those that mediate the movement of lipid particles, such as chylomicrons, from the ER.
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.
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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Otani T, Chepilko SM, Grendell JH, and Gorelick FS. (1998) Codistribution of TAP and the granule membrane protein GRAMP-92 in rat caerulein-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol. 275: G999-1009.
Shugrue CA, Kolen ER, Peters H, Czernik A, Kaiser C, Matovcik L, Hubbard AL, Gorelick F. (1999) Identification of the putative mammalian orthologue of Sec31P, a component of the COPII coat. J Cell Sci. 112: 4547-56.
Gukovskaya AS, Vaquero E, Zaninovic V, Gorelick FS, Lusis AJ|, Brennan ML, Holland S, Pandol SJ. (2002) Neutrophils and NADPH oxidase mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis. Gastroenterology. 122: 974-984.
Lu Z, Karne S, Kolodecik T, and Gorelick FS. (2002) Alcohols enhance caerulein-induced zymogen activation in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol. 282: G501-507.
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.
Chakrabarti S, Kobayashi KS, Flavell RA, Marks CB, Miyake K, Liston DR, Fowler KT, Gorelick FS, Andrews NW. (2003) Impaired membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice. J Cell Biol. 162: 543-9.
Waterford SD, Kolodecik TR, Thrower EC, Gorelick FS. (2005) Vacuolar ATPase regulates zymogen activation in pancreatic acini. J Biol Chem. 280(7): 5430-4.
