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.

Public Health Relevance

. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093491-07
Application #
9251277
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Serrano, Jose
Project Start
2011-09-24
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wen, Li; Javed, Tanveer A; Yimlamai, Dean et al. (2018) Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice. Gastroenterology 155:1250-1263.e5
Boggs, Kristy; Wang, Ting; Orabi, Abrahim I et al. (2018) Pancreatic gene expression during recovery after pancreatitis reveals unique transcriptome profiles. Sci Rep 8:1406
Orabi, Abrahim I; Wen, Li; Javed, Tanveer A et al. (2017) Targeted inhibition of pancreatic acinar cell calcineurin is a novel strategy to prevent post-ERCP pancreatitis. Cell Mol Gastroenterol Hepatol 3:119-128
Huang, Yue; Liu, Chi; Eisses, John F et al. (2016) A supervised learning framework for pancreatic islet segmentation with multi-scale color-texture features and rolling guidance filters. Cytometry A 89:893-902
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
Orabi, Abrahim I; Sah, Swati; Javed, Tanveer A et al. (2015) Dynamic imaging of pancreatic nuclear factor ?B (NF-?B) activation in live mice using adeno-associated virus (AAV) infusion and bioluminescence. J Biol Chem 290:11309-20
Eisses, John F; Criscimanna, Angela; Dionise, Zachary R et al. (2015) Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs. Am J Pathol 185:3304-15
Jin, Shunqian; Orabi, Abrahim I; Le, Tianming et al. (2015) Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-?B, Calcium Signaling, and Calcineurin. Gastroenterology 149:753-64.e11
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
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

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