Molecular pathogenesis of chronic pancreatitis: CFTR and intraductal sensor molecules

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In order to elucidate molecular pathogenesis of chronic pancreatitis, we investigated functional effects of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) and other ion transporters and fibrocystin.1. The entire coding regions of the CFTR gene were analyzed in 65 patients with chronic pancreatitis. Pancreatitis-associated mutations or polymorphisms were identified.2. A finger sweat chloride test, using a highly sensitive chloride electrode, was developed for detecting a high-risk group of chronic pancreatitis.3. A reciprocal regulatory interaction between CFTR and SLC26 transporters (SLC26A3 and SLC26A6) was demonstrated in HEK293 cells.4. Mouse slc26a3 mediated a coupled 2C1^-11HCO_3exchanger, while slc26a6 acted as a 1C^-/2HCO_3exchanger.5. The entire sequence of the guinea pig CFTR gene was determined. Specific RNA interference of the CFTR reduced pancreatic ductal fluid secretion by 50%.6. Short-chain n-alcohol augmented or reduced pancreatic ductal fluid secretion by activating or inhibiting plasma membrane Ca^<2+> channel.7. The Na^+-H^+ exchange played an important role in acidifying pancreatic juice in A ΔF508 CF mice.8. The developmental morphology of the pancreas in polycystic kidney (PKC) rats with a mutation of the fibrocystin gene was examined. Abnormal Ca^<2+> signal and fluid responses were observed in pancreatic ducts isolated from PKC rats.