Abstract The pancreas is extremely sensitive to mechanical injury. Physical manipulation of the pancreas can initiate a series of cellular events leading to premature zymogen activation and eventually pancreatitis. Why the pancreas is so sensitive to mechanical stress and the mechanism by which mechanical force causes pancreatitis were unknown until we discovered that pancreatic acinar cells express mechanically-activated ion channels. The dominant mechanically-activated channel in the pancreas is the cation channel Piezo1. We recently demonstrated that increasing pressure within the pancreatic duct, under conditions that resemble the clinical condition of endoscopic retrograde cholangiopancreatography (ERCP), caused pancreatitis in mice and these effects could be blocked by the Piezo1 antagonist, GsMTx4. Moreover, selective acinar cell-specific genetic deletion of Piezo1 protected mice against pressure-induced pancreatitis. Thus, activation of mechanically sensitive ion channels in pancreatic acinar cells is a previously unrecognized cause of pancreatitis, however, the mechanisms by which Piezo1 activation causes pancreatitis is unknown. As a cation channel, Piezo1 activation produces a rapid influx of extracellular calcium into the cell. Abnormal calcium regulation within the pancreatic acinar cell perturbs zymogen granule and lysosome function and is thought to be an early process in the development of pancreatitis. It is possible that Piezo1 induces pancreatitis by disturbing normal calcium homeostasis. Our preliminary data also indicate that mechanical activation of pancreatic acinar cells disrupts mitochondrial function and stimulates intracellular trypsin activation. Therefore, to assess the pathophysiological role of Piezo1 in the pancreas we will (1) establish the relationship between mechanoactivation and calcium signaling in pancreatic acinar cells, (2) determine the effects of mechanical activation on mitochondrial function and energy metabolism and (3) characterize the contribution of mechanically sensitive ion channel activation to premature zymogen activation and generation of inflammatory mediators in pancreatic acinar cells. We will use a combination of animal, cell biological, and complimentary genetic and pharmacological tools to characterize mechanoactivation of pancreatic acinar cells. These studies will unveil the fundamental mechanisms that cause pancreatitis when pressure is applied to the gland and are relevant to clinical conditions such as surgical manipulation, abdominal trauma, ERCP, and gallstone induced duct obstruction and may provide a novel target for preventing pancreatitis in which manipulation of the gland is anticipated.