Acute pancreatitis is a painful, life-threatening disorder for which there are no targeted therapies. We and others have shown that pathologic calcium signals within the pancreatic acinar cell initiate early pancreatitis responses. Further, we have hypothesized that the calcium-dependent serine, threonine phosphatase calcineurin (CN) is a novel target of this pathological calcium signal. Thus, we propose to use genetic and pharmacologic strategies to (Aim 1) examine the role of CN in clinically relevant experimental models of pancreatitis in vivo [1a, intra-ductal bile acid infusion;1b, post-ERCP;1c, alcohol sensitized], to (Aim 2) determine the contribution of acinar cell CN to pancreatitis in isolated acinar cells using CN inhibitors, adenoviral transfection of CN constructs, and cells from CN transgenics, as well as (Aim 3) in vivo using inducible, acinar cell specific CN transgenics that either endogenously reduce CN activity or delete CN. Our preliminary data support our hypothesis and the feasibility of the planned studies by showing that mice either treated with the CN inhibitor FK506 or genetically deficient in CN (CN A2 KOs) have markedly reduced pancreatitis severity in an in vivo model of intra-ductal bile infusion. We also show that in isolated acinar cells using chemical CN inhibition or cells from CN deficient mice that intra-acinar protease activation is reduced. It is anticipated that these studies (1) will provide a basis for understanding the role of the calcium phosphatase CN in various forms of pancreatitis and (2) will lay the framework for novel clinical trials that target pancreatitis using CN inhibitors.
Acute pancreatitis is a painful and life-threatening disease of the pancreas for which we have no specific treatments. Based on the fact that calcium signals within the pancreas are required for pancreatitis to occur, our proposal seeks to examine the role of an important calcium target protein called calcineurin. We will use animal models of pancreatitis that mimic three common human causes, namely, gallstones, alcohol abuse, and a complication of an endoscopic procedure called an ERCP. We are hopeful that our studies will lead to clinical trials that test the use of already available calcineurin blocking drugs for the treatment of pancreatitis.
|Le, Tianming; Eisses, John F; Lemon, Kathryn L et al. (2015) Intraductal infusion of taurocholate followed by distal common bile duct ligation leads to a severe necrotic model of pancreatitis in mice. Pancreas 44:493-9|
|Eisses, John F; Davis, Amy W; Tosun, Akif Burak et al. (2014) A computer-based automated algorithm for assessing acinar cell loss after experimental pancreatitis. PLoS One 9:e110220|
|Reed, Anamika M; Kolodecik, Thomas; Husain, Sohail Z et al. (2014) Low pH enhances connexin32 degradation in the pancreatic acinar cell. Am J Physiol Gastrointest Liver Physiol 307:G24-32|
|Paredes, Jose L; Orabi, Abrahim I; Ahmad, Taimur et al. (2014) A non-invasive method of quantifying pancreatic volume in mice using micro-MRI. PLoS One 9:e92263|
|Lewarchik, Christopher M; Orabi, Abrahim I; Jin, Shunqian et al. (2014) The ryanodine receptor is expressed in human pancreatic acinar cells and contributes to acinar cell injury. Am J Physiol Gastrointest Liver Physiol 307:G574-81|
|Orabi, Abrahim I; Muili, Kamaldeen A; Javed, Tanveer A et al. (2013) Cluster of differentiation 38 (CD38) mediates bile acid-induced acinar cell injury and pancreatitis through cyclic ADP-ribose and intracellular calcium release. J Biol Chem 288:27128-37|
|Muili, Kamaldeen A; Jin, Shunqian; Orabi, Abrahim I et al. (2013) Pancreatic acinar cell nuclear factor *B activation because of bile acid exposure is dependent on calcineurin. J Biol Chem 288:21065-73|
|Orabi, Abrahim I; Muili, Kamaldeen A; Wang, Dong et al. (2013) Preparation of pancreatic acinar cells for the purpose of calcium imaging, cell injury measurements, and adenoviral infection. J Vis Exp :e50391|
|Raizner, Aileen; Phatak, Uma Padhye; Baker, Kenneth et al. (2013) Acute necrotizing pancreatitis in children. J Pediatr 162:788-92|
|Muili, Kamaldeen A; Wang, Dong; Orabi, Abrahim I et al. (2013) Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin. J Biol Chem 288:570-80|
Showing the most recent 10 out of 14 publications