Pancreatitis is an inflammatory disease of the pancreas. Every year, over 225,000 patients are diagnosed with pancreatitis and over two billion dollars are spent on their care. However, there is currently no treatment for these patients besides conservative management. It is thus necessary that we understand the pathogenesis of this disease so that specific treatment strategies can be developed. The current understanding of the pathogenesis of pancreatitis suggests that events culminating in inflammation of the pancreas are initiated in the acinar cells which synthesize, store, and secrete digestive enzymes in an inactive form. There is evidence that, early in pancreatitis, digestive enzymes are activated intracellularly;these activated digestive enzyme zymogens are believed to be the injury-inciting stimuli. Several publications from our laboratory have shown that early on in pancreatitis, the inactive digestive enzymes co-localize with lysosomal enzymes, following which lysosomal cathepsin B in the co-localized organelles activates trypsinogen. This is corroborated by the fact that inhibiting cathepsin B protects against trypsinogen activation as well as injury during pancreatitis. Until now, cathepsin B in pancreatitis was believed to simply activate digestive enzyme zymogens. Now, however, recent studies in our laboratory have shown that cathepsin B can play a role in the activation of the apoptotic cascade and acinar cell injury during pancreatitis independently of digestive enzyme zymogen activation. This is a new paradigm in the pathophysiology of pancreatitis. Also we have demonstrated for the first time that co-localized organelles become permeabilized in pancreatitis, leading to release of cathepsin B into the cytosol, where it activates the apoptotic cascade. In this grant proposal, we will confirm this exciting and novel finding that, during pancreatitis, cathepsin B released from the co-localized organelles activates apoptosis through a series of in vitro and in vivo studies. Also, the mechanism by which co-localized organelles are permeabalized as well as the mechanism by which cathepsin B activates apoptosis during pancreatic acinar cell will be explored. We have also shown that HSP70 (heat shock protein 70) expression protects against pancreatitis. Our preliminary data suggest that HSP70 does so by preventing co-localization and eventually inhibiting cathespsin B release into the cytosol. Our preliminary studies have also shown for the first time in pancreatic acinar cells that HSP70 attenuates cytosolic calcium elevation in response to caerulein stimulation. Based on these facts as well as on our preliminary data that cytosolic calcium is important for co-localization, we have proposed that novel hypothesis that HSP70 inhibits co-localization in pancreatic acinar cells by attenuating cytosolic calcium and thus protects against injury in pancreatitis. In this grant proposal, we will investigate the mechanism by which HSP70 attenuates cytosolic calcium. Since intracellular calcium is known to be involved in numerous and diverse cellular processes, this aim is significant beyond pancreatitis.
Every year in the U.S., over 225,000 patients are diagnosed with pancreatitis and over two billion dollars are spent on their care. There is currently no treatment for these patients besides conservative management. Thus, we must understand the pathogenesis of this disease so that specific treatment strategies can be developed. Based on the data from studies in our laboratory, we propose the novel hypothesis that cathepsin B plays a major role in the cell death during pancreatitis and that HSP70 protects against pancreatitis by attenuating cytosolic calcium. Once completed, the data generated from the proposed studies will lead to specific therapies against pancreatitis.
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| Dixit, Ajay Kumar; Sarver, Anne E; Yuan, Zuobiao et al. (2016) Comprehensive analysis of microRNA signature of mouse pancreatic acini: overexpression of miR-21-3p in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 311:G974-G980 |
| Talukdar, Rupjyoti; Sareen, Archana; Zhu, Hongyan et al. (2016) Release of Cathepsin B in Cytosol Causes Cell Death in Acute Pancreatitis. Gastroenterology 151:747-758.e5 |
| Banerjee, Sulagna; Saluja, Ashok (2015) Minnelide, a novel drug for pancreatic and liver cancer. Pancreatology 15:S39-43 |
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| Sah, Raghuwansh P; Dudeja, Vikas; Dawra, Rajinder K et al. (2013) Cerulein-induced chronic pancreatitis does not require intra-acinar activation of trypsinogen in mice. Gastroenterology 144:1076-1085.e2 |
| Pasca di Magliano, Marina; Forsmark, Christopher; Freedman, Steven et al. (2013) Advances in acute and chronic pancreatitis: from development to inflammation and repair. Gastroenterology 144:e1-4 |
| Sah, Raghuwansh P; Dawra, Rajinder K; Saluja, Ashok K (2013) New insights into the pathogenesis of pancreatitis. Curr Opin Gastroenterol 29:523-30 |
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