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.
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 study the role of ADAMs, specifically ADAM-10/17 in spreading this local inflammation to systemic levels. We will further evaluate 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. Furthermore, we will evaluate the role of anti-microbial `Neutrophil Extracellular Traps' or NETs, in acinar cell injury. We are also uniquely poised, using our T7-KO mice, to answer the question if trypsin activation has any role in neutrophil induced acinar cell injury, whether caused by NETs or otherwise.
| Sethi, Vrishketan; Kurtom, Saba; Tarique, Mohammad et al. (2018) Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response. Gastroenterology 155:33-37.e6 |
| 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 |
| 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 |
| Ganguly, Siddhartha; Home, Trisha; Yacoub, Abdulraheem et al. (2015) Targeting HSF1 disrupts HSP90 chaperone function in chronic lymphocytic leukemia. Oncotarget 6:31767-79 |
| Sah, Raghuwansh P; Garg, Sushil K; Dixit, Ajay K et al. (2014) Endoplasmic reticulum stress is chronically activated in chronic pancreatitis. J Biol Chem 289:27551-61 |
| 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 |
| 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 |
| Sah, Raghuwansh P; Garg, Pramod; Saluja, Ashok K (2012) Pathogenic mechanisms of acute pancreatitis. Curr Opin Gastroenterol 28:507-15 |
| Sah, Raghuwansh P; Saluja, Ashok (2011) Molecular mechanisms of pancreatic injury. Curr Opin Gastroenterol 27:444-51 |
Showing the most recent 10 out of 16 publications
