Relative Contribution of Trypsin and Inflamation in Acute and Chronic Pancreatitis

Project: Research project

Project Details

Description

Abstract Pancreatitis, an inflammatory disease of pancreas, leads to more than 300,000 admissions to hospitals in the United States alone. Despite decades of research there is no specific therapy for pancreatitis. While the inflammation during acute pancreatitis is initiated in acinar cells, over disease course the inflammation spills into systemic circulation. Uncontrolled systemic inflammation during acute pancreatitis can lead to Systemic Inflammatory Response Syndrome (SIRS) and multi-organ failure, which is the primary cause of morbidity and mortality. Thus strategies to control inflammation will lead to development of specific therapy for acute pancreatitis. In the current proposal we will evaluate the early intra-acinar events in pancreatitis that lead to activation of signaling pathways that mediate local inflammation, eventually resulting in disease development. In the first aim, we will evaluate the role of ADAMs, specifically ADAM-10/17 in spreading this local inflammation to systemic levels. ADAMs are Zn2+ - dependent proteases that proteolytically cleave a wide variety of membrane-bound proteins. Among these, ADAM-10 and -17 have been implicated in multiple inflammatory disorders but their role has not been evaluated in pancreatitis. Intriguingly, our preliminary data suggest that treatment with ADAM-10/17 inhibitor in a therapeutic setting, i.e. after initiation of injury, leads to decrease in pancreatic and lung injury and inflammation in caerulein model of severe acute pancreatitis. As most of the studies in acute pancreatitis perform prophylactic intervention, which is not clinically significant, the current proposal is focused on evaluating this translationally relevant observation that has the potential of being developed into a therapeutic strategy for pancreatitis. In the next aim, we will study how induction of pancreatitis may result in activation of ER stress in the acinar cells and how this may lead to activation of signaling pathways like AP-1 and NF-kB that are known to be associated with inflammation. We will also evaluate the role of anti-microbial `Neutrophil Extracellular Traps' or NETs, in acinar cell injury in the third aim, which will help us understand the vicious cycle of inflammation and injury in pancreatitis. Since we are in possession of the unique T7 KO mice, we will be in a position to evaluate the role of trypsin in these early intra-acinar events that will eventually help us in understanding the local and systemic inflammation in the context of pancreatic injury.
StatusActive
Effective start/end date8/1/113/31/22

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $540,673.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $450,578.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $544,405.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $346,128.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $450,578.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $434,808.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $107,112.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $544,403.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $507,842.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $544,403.00

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