In the United States, more than 300,000 patients are admitted per year and over 2 billon dollars spent on their care. Despite the enormity of the disease, there is currently no targeted therapy, primarily due to incomplete understanding of pathophysiological mechanisms. The current paradigm of both acute and chronic pancreatitis revolves around intra-acinar activation of trypsin, which is believed to be central to both acinar cell injury and inflammation. However, evidence in support of the 'trypsin central'hypothesis can best be described as correlational and circumstantial. Thus far, no direct evidence exists to show that the premature activation of trypsinogen, observed early during pancreatitis, is casually responsible for the pathogenesis of acute pancreatitis. The exciting findings from our preliminary studies (using our newly developed cationic trypsinogen and cathepsin B knockout mice) aimed at elucidating the role of trypsin in pathogenesis of pancreatitis suggest that trypsin partially contributes to pancreatic injury in acute pancreatitis but is not required for development of chronic pancreatitis. This grant proposal is geared towards elucidating the actual contributions of intra-acinar activated trypsin and inflammatory pathways in acute and chronic pancreatitis and offers a unique opportunity to reconcile research of the last decades.
In aim 1, we will evaluate the role of trypsin in pancreatic injury during acute pancreatitis using newly developed cationic trypsinogen knockout mice in several in vivo and in vitro models of the disease.
In aim 2, we will study the role of inflammation in pancreatic and systemic injury during acute pancreatitis. This will involve use of cationic trypsinogen knockout mice in combination with mice harboring variants of NFkB signaling and creating mice with deletion of cationic trypsinogen and disrupted NFkB signaling.
In aim 3, we will determine the role of trypsin in pathogenesis of chronic pancreatitis using two different models.
In aim 4, the role of repeated inflammatory insult in the absence of trypsin activation will be investigated in chronic pancreatitis using cationic trypsinogen deleted and NFkB signaling defective mice. Successful completion of the proposed studies will uncover novel mechanisms for the pathogenesis of acute and chronic pancreatitis for which currently we do not have targeted therapeutics. A better understanding of the complex mechanisms will be useful for developing future novel treatments.

Public Health Relevance

Pancreatitis, in both its acute and chronic forms causes significant morbidity, mortality and more than 300,000 hospitalizations per year. There is no specific therapy available for this disease. Premature activation of the digestive protease trypsin within pancreas, either because of pathological events or due to genetic defects in the gene is considered to be the key event in initiation of pancreatitis. However, the evidence supporting the role of trypsin is circumstantial at best. Our preliminary data using mice in which trypsin activation is not observed either due to lack of precursor (cationic trypsinogen) or due to lack of cathepsin B, the enzyme responsible for the activation show that trypsin activation is only partially responsible for the tissue damage observed in acute pancreatitis and does not affect the tissue injury in chronic pancreatitis. In this grant, we propose to investigate the role of trypsin activation in acute and chronic pancreatitis with a focus on its role in acinar cell injury and its relationship to activation of inflammatory pathways as well as its overall contribution to pancreatic injury. We will use multiple animal models of both acute and chronic pancreatitis to achieve these aims. With the successful completion of the proposed studies, we hope to achieve better insights into the mechanism of disease, which will help in design of targeted therapeutics for this important disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093047-02
Application #
8304204
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Serrano, Jose
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$450,578
Indirect Cost
$152,182
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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
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

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