Pancreatitis is an inflammatory disease of the pancreas. The U.S. alone sees over 300,000 hospital admissions for acute pancreatitis annually with costs exceeding $2B. However, there is currently no specific therapy for this disease, a lamentable situation arising from our incomplete understanding of its pathophysiology. In part, this situation can be ascribed to the fact that, due to the non-availability of human acinar tissue for experimentation, most of our current knowledge of the pathophysiology of pancreatitis arises from experimental animal models. However, our preliminary data as well as other published studies indicate that there are significant differences in the physiology and pathobiology of acinar cells between humans and rodents. Such information accentuates the urgent need to re-access data generated from rodent models in models which truly reflect human disease. This is further reinforced by the negative outcomes of the clinical trials using the information learnt from experimental animal models. Recently, the advent of endocrine pancreas transplantation programs has made healthy human exocrine pancreatic tissue from donor organs available for in vitro experiments. There are only a handful of such transplantation centers in the US, and to successfully harvest and study human acini in-vitro requires an experienced exocrine pancreas lab. At our center we are uniquely poised to fulfill both pre-requisites. In the current proposal, we intend to utilize acinar cells harvested from pancreata of healthy donors to study and validate basic tenets in the physiology and pathophysiology of human exocrine pancreas. The studies proposed in the current grant will first confirm the tenets of stimulus secretion coupling in human acinar cells, since these principles form the backbone of studies on pathophysiology of pancreatitis. Next, the pathophysiology of early acute pancreatitis will be studied in two different in vitro models of acute pancreatitis in human acinar cells: hyperstimulation model and the more clinically apt model of biliary pancreatitis. We believe that the data generated through the experiments proposed in the current grant proposal will form the basis, in the future, of directed research applicable to the pathophysiology of acute pancreatitis in humans and lead to accelerated development of specific therapy for its prevention and treatment.

Public Health Relevance

Pancreatitis is an inflammatory disease. Every year in the U.S. alone, more than 300,000 patients are diagnosed with pancreatitis and over two billion dollars are spent on their care. There is currently no specific therapy for these patients, a lamentable situation arising from our incomplete understanding of its pathophysiology. Due to the paucity of the availability of human pancreatic tissues for experimentation, most of our information about biology and pathobiology of the pancreatic acinar cells comes from studies in rodents. However, numerous studies have suggested that there are significant differences in the physiology of human and rodent acini. Studies pertaining to human pancreatic acinar cells have been hampered due to a lack of access to healthy human tissue. Recently, however, the advent of endocrine pancreas transplantation programs has made healthy human exocrine pancreatic tissue from donor organs available for in vitro experiments. There are only a handful of such transplantation centers in the US, and to successfully harvest and study human acini in vitro requires an experienced exocrine pancreas lab. At our center, we are uniquely poised to fulfill both pre-requisites. In the current proposal, we intend to utilize acinar cells harvested from pancreata of healthy donors to study and validate basic tenets in the physiology and pathophysiology of human exocrine pancreas. Once completed, the data generated from the proposed studies will lead to accelerated development of specific therapies against pancreatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK092145-02
Application #
8228049
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (04))
Program Officer
Serrano, Jose
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$328,425
Indirect Cost
$110,925
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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; Saluja, Ashok K (2011) Trypsinogen activation in acute and chronic pancreatitis: is it a prerequisite? Gut 60:1305-7
Loganathan, Gopalakrishnan; Dawra, Rajinder K; Pugazhenthi, Subbiah et al. (2011) Insulin degradation by acinar cell proteases creates a dysfunctional environment for human islets before/after transplantation: benefits of ?-1 antitrypsin treatment. Transplantation 92:1222-30
Sah, Raghuwansh P; Saluja, Ashok (2011) Molecular mechanisms of pancreatic injury. Curr Opin Gastroenterol 27:444-51
Dawra, Rajinder; Sah, Raghuwansh P; Dudeja, Vikas et al. (2011) Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterology 141:2210-2217.e2