Preliminary data supports an association between activation of stress-activated protein kinase pathway, expression of chemokines, and secretagogue-induced experimental pancreatitis. This work is designed to explore mechanisms and interrelationships between events in these pathways and their role in pancreatitis.
The first aim i s designed to test the hypothesis that chemokines are specifically and rapidly induced in acinar cells by treatments that induce pancreatitis utilizing the secretagogue hyperstimulation model, intraductal injection of bile salt and protease solutions, and ischemia/reperfusion models of pancreatitis.
The second aim explores the hypothesis that activation of the stress kinase pathway is necessary and sufficient for the stimulation of chemokine gene expression. This will utilize both the in vivo animal models of pancreatitis, as well as in vitro studies with dispersed pancreatic acinar cells. The latter allows various manipulations for activation and inhibition of stress kinase signalling cascades, as well as the adenoviral-mediated gene delivery of constitutively-active or dominant-negative signalling genes.
The third aim tests the hypotheses that NFkB is involved in chemokine gene expression in pancreatic acinar cells. This again utilizes both in vivo and in vitro approaches with various manipulations of NFkB and IkB.
The final aim tests the hypothesis that modification of chemokine expression in vivo will influence the severity of pancreatitis. This will attempt to utilize adenoviral vectors to directly express the specific chemokines in the pancreas in vivo and explore effects on the characteristics of pancreatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052067-03
Application #
6164541
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
1998-05-10
Project End
2002-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
3
Fiscal Year
2000
Total Cost
$196,437
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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