Protein Kinase D1 as a switch from acute to chronic pancreatitis

PROJECT SUMMARY/ABSTRACT Acute pancreatitis, if it doesn’t resolve, can further develop into a chronic condition. Resulting chronic pancreatitis is characterized by presence of inflammatory macrophages, fibrosis, and loss of acinar cells. Moreover, it represents a risk factor for pancreatic cancer. The cellular and molecular mechanisms that mediate the transition from acute to chronic pancreatitis are ill-defined, and efficient therapeutic treatment methods for chronic pancreatitis are lacking. In this proposal, it is our hypothesis that Protein Kinase D1 primes acinar cells to produce factors that prevent acute pancreatitis from resolving and generates a chronic condition. We further hypothesize that the resulting chronic pancreatitis can be targeted with PKD inhibitors. To test this we will: Determine how PKD1 expression in acinar cells can generate an environment that is favorable for developing chronic pancreatitis (Specific Aim 1); and utilize our acinar cell- targeted animal models to determine the effects of PKD1 on development and resolution of chronic pancreatitis (Specific Aim 2). Successful completion of this project will define the role of activated PKD1 in altering pancreatic acinar cells in a way that they can facilitate the transition of acute pancreatitis to a chronic state. We will define how these molecular changes affect cells in the pancreatic environment and the immune landscape in the pancreas. Eventually, we will determine if inhibition of PKD1 in vivo can resolve chronic pancreatitis. This will lay the groundwork of developing targeted treatment strategies for pancreatitis based on inhibition of PKD1 or downstream signaling events.