1Chapter 1 The changing paradigm of chronic pancreatitis

Identification of mutations that lead to pancreatitis and its complications has revolutionized our understanding of pancreatic diseases. Integrating the pathologic effect of a gene mutation on the function of key proteins, and understanding the role of these proteins from a systems biology approach will lead to changes in every aspect of medical care. With few exceptions, all forms of pancreatitis are traced back to disregulation of trypsin. Trypsin controls trypsin, and calcium flips the switches between trypsin mediated activation and inactivation. Mutations in the calcium regulatory domains of trypsinogen (PRSSI) lead to calcium-independent facilitation of activation or prevention of inactivation. Mutations in the SPINK1 gene lower the threshold for unregulated trypsin activation of itself and other zymogens. Mutations in CFTR, the molecule that regulates pancreatic duct secretion, diminish the ability to flush activated trypsin into the intestine, especially in the presence of distal duct resistance. Mutated PRSS1, SPINK1 and CFTR genes are susceptibility factors for recurrent acute pancreatitis (RAP), an