Pancreatitis is a major life-threatening health problem. An important iatrogenic cause of pancreatitis occurs after a common GI procedure called an endoscopic retrograde cholangiopancreatography (ERCP). Although recent pancreatic duct stenting and anti-inflammatory prophylaxis have improved post-ERCP pancreatitis (PEP) outcomes, PEP is still a formidable problem that is recognized by NIDDK as a disease of interest. Furthermore, the molecular mechanisms underlying PEP remain elusive. Our lab actively examines the role of aberrant Ca2+ signals in the pathogenesis of pancreatitis. In preliminary data, we have identified that the radiocontrast (RC) instilled into the pancreatico-biliary ducts during ERCP triggers robust cytosolic Ca2+ signals in pancreatic acinar cells and induces the activation of the Ca2+ phosphatase calcineurin (Cn). Thus the overall goal of the proposal is to examine the role of Ca2+ and Cn in mediating PEP, with emphasis on RC exposure. Our overarching hypothesis is that a primary mechanism for PEP is the induction of aberrant pancreatic acinar cell Ca2+ signals and activation of Cn.
Our specific aims are (Aim 1) to examine how RC exposure to the pancreas (1a) induces aberrant acinar cell Ca2+ signals and (1b) activates Cn;
(Aim 2) to examine whether Cn activation by RC is critical to inducing (2a) NF- ?B inflammatory signals and (2b) pancreatic injury;
and (Aim 3) to determine (3a) whether acinar cells are a critical site of Cn activation during PEP and (3b) whether targeted delivery of Cn inhibitors to the pancreas will prevent PEP. We believe that the proposal will provide a solid basis to examine the role of Ca2+ and Cn pathways in mediating PEP and pancreatitis, with the anticipated goal to devise targeted therapies for preventing PEP and potentially treating pancreatitis with Cn inhibitors.
. Despite some inroads, post-ERCP pancreatitis (PEP) is still a major problem. Thus in the current proposal, we will determine, in both a test tube of fresh human and mouse pancreas cells and in the whole mouse, how a PEP-related trigger, such as exposure of the pancreas to the radiocontrast dye used in ERCPs, induces abnormal early pancreatitis events involving calcium and the subsequent activation of a calcium protein called calcineurin.
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