ABSTRACT The principal objective of this grant proposal entitled “Mechanisms of trypsin activation in pancreatitis“ is to identify the process by which the digestive protease trypsin becomes activated inside the pancreas and initiates pancreatitis. The premature, ectopic activation of trypsinogen to trypsin is one of the earliest events in the development of pancreatitis. However, the mechanism of intrapancreatic trypsin activation has remained contentious as animal experiments and human genetic studies pointed to different activation pathways. Thus, trypsinogen may be activated by cathepsin B but it can also undergo autoactivation, when trypsin activates trypsinogen. The respective contribution of these two mechanisms to trypsin activation associated with pancreatitis onset is unknown. To address this knowledge gap, we propose three distinct scenarios of trypsinogen activation. 1) In the absence of increased trypsinogen autoactivation caused by genetic mutations, cathepsin B can induce significant intrapancreatic trypsin activation, without affecting pancreatitis severity. (2) If genetic mutations in trypsinogen moderately increase autoactivation, severity of experimentally-induced pancreatitis will depend on the degree of cathepsin B-mediated trypsinogen activation. (3) Finally, if a genetic change that causes robust trypsinogen autoactivation, age of onset and severity of spontaneous pancreatitis is determined by cathepsin B-mediated trypsinogen activation. In this grant proposal, we will test each of these three pathological circumstances using unique mouse models with trypsinogen mutations. Successful completion of the proposed project will offer fresh mechanistic insight into the pathogenesis of pancreatitis and will facilitate the development of novel therapeutic and preventive approaches.

PROJECT NARRATIVE This grant proposal investigates how the digestive enzyme trypsin becomes activated inside the pancreas and initiates the inflammatory disease pancreatitis. The scientific approach uses novel genetically modified mice in which trypsin activation has been altered. The results from the proposed experiments will advance our understanding of the disease and aid in the development of therapeutic interventions.