骨桥蛋白干预胆固醇代谢影响胆囊胆固醇结石形成的机制探讨

目前胆石成因的研究热点为具有成核活性蛋白质的功能研究，方法多采用对基因敲除或siRNA沉默蛋白表达的动物模型观察。我们在前一项自然科学基金的资助下,发现骨桥蛋白(osteopontin,OPN)在胆囊胆固醇结石的形成过程中发挥着重要作用，然而其机制不明。有资料显示，OPN与肝脏胆固醇代谢有着密切关系，其是否通过干预胆固醇代谢而影响胆固醇结石形成以及其机制值得深入研究。本研究旨在通过慢病毒介导短发夹RNA（short hairpin RNA，shRNA）沉默小鼠OPN表达（该模型已建立），观察各项胆固醇相关代谢指标的变化，并观察各项胆固醇代谢调节蛋白的变化情况，以探讨OPN通过干预胆汁胆固醇代谢而影响胆固醇结石的形成以及其可能机制；并观察动物模型以及胆结石患者服用溶石药物（熊去氧胆酸）以及降胆固醇药物（依泽替米贝，Ezetimibe）前后体内OPN的变化，探讨OPN的潜在临床价值。

The research on the function of some nucleation active proteins has been raised as a highlight in the field of gallstone formation. Those researches always base on a gene knock-out or siRNA silencing protein expression animal model. We have demonstrated osteopontin(OPN) plays an important role in the formation of gallstone supported by a former National Natural Science Fund. But the mechanism of OPN involved in gallstone formation still remains unclear. Some data show that OPN impact on hepatic cholesterol metabolism. Further research need to be carried on if OPN involved in gallstone formation through the impact on hepatic cholesterol metabolism. In this research, a Lentivirus-mediated short hairpin RNA targeting OPN mouse model will be established. The cholesterol metabolism indicators will be observed. The change of proteins regulating cholesterol metabolism will also be observed. All these research will demonstrate if OPN involved in gallstone formation through the impact on hepatic cholesterol metabolism and its exact mechanism. Furthermore, Ursodeoxycholic acid and Ezetimibe will be given to the mouse model or patients with cholelithiasis. And the change of OPN will be observed to discover the potential clinical value of OPN.