ROR-α agonist as a novel treatment and prevention of pancreatitis

Pancreatitis is a known cause of mortality. Treatments for pancreatitis are limited and are only supportive. The overall mortality rate in acute pancreatitis is 10-15%. The incidence of acute pancreatitis has been increasing over the last 20 years at an average annual percent change of 3%. Thus, a specific treatment for pancreatitis is of great need. Recent reports suggest that FGF21 can ameliorate acute pancreatitis. FGF21 is a protein which belongs to the fibroblast growth factor family and mostly produced and secreted by the liver. However, it can also be secreted by the pancreas and by the white adipose tissue. FGF21 is positively regulated by the RORα transcription factor. In this research, we propose to assess whether a RORα agonist that we identified by screening compounds that act against Non-alcoholic steatohepatitis (NASH) in mice, and which we found to increase FGF21 expression, can be used as a treatment for pancreatitis. In addition, we shall investigate whether increased FGF21 expression can also be used to prevent pancreatitis caused following Endoscopic Retrograde CholangioPancreatography (ERCP). We have already established a Caerulein-induced pancreatitis model in mice, and we are currently establishing a second model, based on alcohol-induced pancreatitis. In both models, we shall treat mice with our RORα agonist compound, and assess pancreatitis readout measures. Next, we shall validate the compound’s effect in human cells and also evaluate the efficacy of FGF21 as a prognostic biomarker for pancreatitis.