胆道梗阻后肠道分泌和吸收功能的改变及其细胞分子机制研究

胆道梗阻后由于肝脏胆汁淤积肝功能受损以及缺少胆汁酸进入肠道这两大主要因素，会导致一系列病理生理改变。胆道梗阻后有关肠道分泌和吸收功能的研究甚少。近10余年的研究表明胆汁酸是一个重要的调节分子，可通过核受体FXR和PXR以及ERK1/2、JNK1/2细胞信号转导通路调控蛋白质和基因表达，进而调节肠道的生理功能。我们前期研究表明胆道梗阻可以导致肠道氯离子分泌和葡萄糖吸收功能的改变。在本项目中，我们将建立小鼠胆道梗阻模型，进一步分析肠道氯离子分泌和糖吸收功能的变化，并通过体内和体外研究阐明胆汁酸特异性核受体、细胞信号调节分子和细胞因子在胆汁酸对肠道氯离子转运及糖吸收的影响中的作用及机制，明确胆道梗阻病人肠粘膜氯离子转运及葡萄糖转运蛋白表达水平的异常及其与临床病理特征的关系，从而深入探讨胆道梗阻后肠道氯离子分泌和葡萄糖吸收功能的变化及其细胞分子机制，有望为胆道梗阻后并发症的防治提供新的理论基础。

Biliary obstruction, which is characterized by inducing intestinal bile deficiency and accumulation of biliary compounds in the body, is a common surgical condition and may cause multiple pathophysiologic changes. However, intestinal secretion and absorption function under the condition of biliary obstruction was less studied. It has been discovered that bile acids are regulatory molecules in the previous studies. Bile acids could regulate intestinal physiologic functions via activating specific nuclear receptors (FXR, PXR) and cell signaling pathways (ERK1/2, JNK1/2) to induce the alterations of numerous protein and gene expressions. Our previous studies demonstrated that biliary obstruction could alter intestinal Cl- secretion and glucose absorption. In the present study, we aimed to further analyse the alterations of intestinal Cl- secretion and glucose absorption through using an experimental model of murine biliary ligation and investigate the role of bile acids specific nuclear receptors, cell signaling regulators and cytokines in biliary obstruction-induced intestinal Cl- secretion and glucose absorption alterations through in vitro and in vivo experiments, and the correlation between the expression levels of intestinal mucosal Cl- transport protein, glucose transport protein and clinical features in patients with biliary obstruction. Thus, this study will elucidate the alterations of intestinal Cl- secretion and glucose absorption function after biliary obstruction and its underlying cellular and molecular mechanisms, and may provide a new strategy for preventing biliary obstruction complications.