Acute pancreatitis is a sometimes fatal human disease in which the pro-enzymes synthesized in the pancreatic acinar cells are activated inside the cells (rather than after they have been secreted into the gut) and digest the pancreatic tissue (rather than the food in the gut). It is mostly caused by gallstones or excessive alcohol intake. Repeated attacks may lead to chronic pancreatitis, which increases markedly the risk of developing pancreatic cancer. There is currently no specific therapy for pancreatitis. We have recently identified molecules in the acinar cells responsible for the excessive intracellular Ca2+ release elicited by agents causing pancreatitis and been able to knock-out of these molecules and thereby prevent the fatal intracellular protease activation. Furthermore, we have discovered that a normally present intracellular molecule, calmodulin (CaM), exerts a protective action and found that application of a membrane-permeable Ca2+-like peptide can boost this protection. We now plan to test systematically the CaM-dependent mechanisms for inhibiting excessive intracellular Ca2+ release elicited by all the major known agents inducing pancreatitis. We shall specifically test the ability of Ca2+-like peptides to protect against intracellular protease activation using realistic mouse models of the disease. We also plan novel studies of a special cell type, namely the pancreatic stellate cell (PSC). Activated PSCs drive development of chronic pancreatitis and are responsible for production of the cancer-promoting stromal matrix. Intracellular Ca2+ is involved, but the mechanisms of Ca2+ transport and function in PSCs are obscure and essentially nothing is known about nervous control. Building on our experience with Ca2+- dependent control of the acinar cell function, we shall study nervous and chemical control of PSCs in mouse pancreatic lobules and test procedures to inhibit their excessive secretion of cancer-promoting materials.