Molecular pathogenesis of chronic pancreatitis: CFTR and intraductal sensor molecules

为了阐明慢性胰腺炎的分子发病机制，我们研究了囊性纤维化跨膜传导调节因子（CFTR）和其他离子转运蛋白以及纤维囊素突变对功能的影响。分析了65例慢性胰腺炎患者CFTR基因的全编码区。胰腺炎相关的突变或多态性被确定。使用高灵敏度氯电极的手指汗液氯化物试验，被用于检测慢性胰腺炎的高危人群。在HEK293细胞中证实了CFTR和SLC26转运体（SLC26A3和SLC26A6）之间的相互调节作用。小鼠slc26a3介导一个偶联的2C1^- 11hco_3交换体，而slc26a6介导一个1C^-/ 2hco_3交换体。测定了豚鼠CFTR基因的全序列。特异性RNA干扰CFTR使胰管液分泌减少50%。短链正醇通过激活或抑制质膜Ca^<2+>通道增加或减少胰管液分泌。Na^+-H^+交换在A ΔF508 CF小鼠胰液酸化中起重要作用。研究了纤维囊蛋白基因突变多囊肾大鼠胰腺的发育形态。PKC大鼠胰管Ca^<2+>信号异常，血流反应异常。

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.