Repeated or prolonged injury to the pancreas leads to loss of normal exocrine and endocrine tissue and pancreatic fibrosis. Fibrosis of the pancreas which can lead to stricturing of the common bile and pancreatic ducts with resultant duct obstruction. Importantly, pancreatic duct obstruction may contribute to the development of chronic pancreatitis even in the absence of other pancreatic injury. For example, increased pancreatic duct pressure itself can cause chronic pancreatitis and pancreatic fibrosis. Therefore, it appears that the pancreas can sense pressure and pressure causes pancreatic injury. Pancreatic fibrosis results from the deposition of extracellular matrix by activated pancreatic stellate cells (PSCs). Under normal conditions PSCs reside in the pancreas in a quiescent state but are converted to an active state when the pancreas is injured. Activated PSCs secrete collagen and other proteins to cause fibrosis. The observation that pancreatic duct obstruction and pressure, itself, can induce pancreatic fibrosis even in the absence of inflammation, led us to ask if PSCs can sense pressure? And if so, how? The recent discovery that pressure sensitivity could be conveyed through cell surface, mechanically-activated ion channels led us to examine these proteins in the pancreas. We recently discovered that the mechanically- activated ion channel Piezo1 is highly expressed in PSCs. Our preliminary data indicate that pressure sensitivity in the pancreas is conveyed by Piezo1 and that Piezo1 activation may be linked to PSC activation. Therefore, we hypothesize that pressure within the pancreas causes pancreatic fibrosis by stimulating Piezo1 in pancreatic stellate cells (PSCs). In the current proposal, we will determine if this pathway is the mechanism linking pancreatic duct obstruction with pancreatic fibrosis. We believe these studies will identify a novel mechanism for the development of pancreatic fibrosis. Moreover, we will determine if blocking mechanically activated ion channels and their signaling pathways protect against pancreatic fibrosis. Overall, this project will yield novel insights into the initiation of pancreatic fibrosis and could unveil a novel target for preventing its complications.
Prolonged injury to the pancreas causes pancreatic fibrosis and is associated with an increased risk of pancreatic cancer. We recently discovered that pancreatic stellate cells, which are the source of fibrosis, react to pressure through the mechanically-activated ion channel, Piezo1. The current proposal will determine if blocking Piezo1 prevents stellate cell activation and protects against pancreatic fibrosis. These studies could lead to new therapies for chronic pancreatitis.
