Fred Gorelick, MD

Henry J. and Joan W. Binder Professor of Medicine (Digestive Diseases) and of Cell Biology; Director Investivative Gastroenterology NIH T32, Internal Medicine; Deputy Director, Yale M.D., Ph.D. Program

Research Interests

Autophagy; Cell Biology; Digestive System Diseases; Gastrointestinal Diseases; Pancreatic Diseases; Pancreatitis; Pancreas, Exocrine; AMP-Activated Protein Kinases; Proteolysis

Research Organizations

Cell Biology: Membrane Traffic

Internal Medicine: Digestive Diseases | Liver Center

Office of Cooperative Research

Research Summary

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. We have also collaborated on work showing that a new survival factor, renalase, has a critical role in both acute pancreatitis and pancreatic cancer. Renalase may enhance cell survival by activating a plasma-membrane calcium pump. Finally, we believe that specific estrogen receptors might account for greater acute pancreatitis severity in young females and could be targeting therapeutically. We plan to pursue these studies using rodents models of pancreatitis, human acinar cells, and to collaborate with clinical investigators to examine these pathways in patients to examine the following issues.

1) The effect of AMPK activators in cellular and animal models of acute pancreatitis

2) The role of plasma protein, renalase, in reducing injury in pancreatitis and as a driver for pancreatic cancer

3) The potential of serum renalase levels to be biomarkers of acute pancreatitis severity and pancreatic cancer stage. 

4) The role of estradiol and estrogen receptors in acute pancreatitis models.

Selected Publications

Full List of PubMed Publications

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Contact Info

Fred Gorelick, MD
Mailing Address
Internal MedicinePO Box 208056
333 Cedar Street

New Haven, CT 06520-8056

Curriculum Vitae