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, survival factor, renalase, plasma-membrane calcium pump
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. Our recent focus has turned to the role of the survival factor, renalase (RNLS), a protein discovered by Dr. Desir and co-workers at Yale that modulates acute injury and inflammation. RNLS may enhance cell survival by activating a plasma-membrane calcium pump. We have found that RNLS reduces the severity of acute experimental pancreatitis. We have also found that it can be a driver for select cancers, including pancreatic adenocarcinoma. Efforts are underway to develop RNLS agonists and antagonists for therapeutic use. We have also found that plasma levels of RNLS are dynamically regulated and might be useful biomarkers in the setting of inflammatory injury as well as select cancers. 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 effects of renalase in models of acute acute pancreatitis
2) Regulation of plasma renalase levels during acute injury and the function of plasma renalase binding proteins
2) Renalase as a driver for pancreatic cancer and its function in pancreatic cancer precursor lesions
3) The potential of serum renalase levels to be biomarkers in pancreatic cancer that corresponds to tumor stage.
4) The role of estradiol and estrogen receptors in acute pancreatitis models.
Autophagy; Cell Survival; Cell Biology; Digestive System Diseases; Gastrointestinal Diseases; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Pancreas, Exocrine; Proteolysis