Calcineurin in pancreatitis

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DESCRIPTION (provided by applicant): 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.