It is generally believed that acute pancreatitis is triggered by the intra-acinar cell activation of digestive enzyme zymogens including trypsinogen. However, the mechanisms responsible for intra-acinar cell zymogen activation and the subsequent events which determine the severity of pancreatitis are poorly understood. The proposed studies will build on our previous observations to explore these issues.
The Specific Aim #1 studies will examine the relationship between digestive zymogen/lysosomal hydrolase co-localization and zymogen activation. We will determine if co-localization leads to or results from zymogen activation.
The Specific Aim #2 studies will define the Ca2+-dependence of intra-acinar cell trypsinogen activation and the question of whether a rise in [CA2+]i is, by itself, sufficient to cause intra-acinar cell zymogen activation.
The Specific Aim #3 studies are based on our recent finding that a phosphoinositide-3-kinase (PI3K) plays a central role in mediating zymogen activation. We will define the class of PI3K which is involved and elucidate the mechanism(s) by which it mediates zymogen activation. Finally, our Specific Aim #4 studies will build upon our recent findings which suggest that pancreatic acinar cells may possess proteinase-activated receptors (PARs) that regulate acinar cell expression of inflammatory mediators. We will determine if, in fact, acinar cells display PAR-2 and/or PAR-4 receptors, whether those receptors respond to other proteases in addition to trypsin, and whether PAR-mediated chemokine/cytokine expression is dependent upon changes in [CA2+]i homeostasis. Taken together, the studies proposed in this application will advance our understanding of the cellular basis for pancreatitis and of the events which regulate the severity of pancreatitis. They will identify potential targets for therapeutic intervention in this frequently devastating disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
United States
Zip Code
Perides, George; Weiss, Eric R; Michael, Emily S et al. (2011) TNF-alpha-dependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice. J Biol Chem 286:13327-35
Perides, George; Laukkarinen, Johanna M; Vassileva, Galya et al. (2010) Biliary acute pancreatitis in mice is mediated by the G-protein-coupled cell surface bile acid receptor Gpbar1. Gastroenterology 138:715-25
Laukkarinen, Johanna M; Weiss, Eric R; van Acker, Gijs J D et al. (2008) Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis. J Biol Chem 283:20703-12
Frossard, Jean-Louis; Steer, Michael L; Pastor, Catherine M (2008) Acute pancreatitis. Lancet 371:143-52
Laukkarinen, Johanna M; Van Acker, Gijs J D; Weiss, Eric R et al. (2007) A mouse model of acute biliary pancreatitis induced by retrograde pancreatic duct infusion of Na-taurocholate. Gut 56:1590-8
Van Acker, Gijs J D; Weiss, Eric; Steer, Michael L et al. (2007) Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 292:G1738-46
Van Acker, Gijs J D; Perides, George; Weiss, Eric R et al. (2007) Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis. J Biol Chem 282:22140-9
Song, Albert M; Bhagat, Lakshmi; Singh, Vijay P et al. (2002) Inhibition of cyclooxygenase-2 ameliorates the severity of pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol 283:G1166-74
Frossard, J-L; Bhagat, L; Lee, H S et al. (2002) Both thermal and non-thermal stress protect against caerulein induced pancreatitis and prevent trypsinogen activation in the pancreas. Gut 50:78-83
Van Acker, Gijs J D; Saluja, Ashok K; Bhagat, Lakshmi et al. (2002) Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity. Am J Physiol Gastrointest Liver Physiol 283:G794-800

Showing the most recent 10 out of 43 publications