肝脏胆固醇代谢是影响胆囊胆固醇结石形成的关键因素，也是本领域研究热点。申请人前期工作发现骨桥蛋白（OPN）可通过干预肝脏胆固醇代谢影响胆囊胆固醇结石形成，且该作用与CYP7A1有关；但OPN调节CYP7A1表达的确切机制尚不明确。CYP7A1是肝脏胆固醇分解限速酶，其在转录水平受PI3K/AKT、MEK/ERK和JNK等通路调控；OPN是细胞外基质蛋白，需通过结合整合蛋白激活下游通路发挥生物学功能；FAK是整合蛋白传递信号的关键一员；预实验中FAK抑制剂可阻断OPN下调CYP7A1表达这一现象。由此提出假说：OPN通过FAK激活下游通路下调CYP7A1表达，进而影响胆囊胆固醇结石形成。本研究拟从细胞水平阐明OPN下调CYP7A1表达影响胆囊胆固醇结石形成的确切机制，并从动物以及人体组织水平加以验证。结果将进一步明确OPN影响胆囊胆固醇结石形成的机制，为防治胆囊胆固醇结石提供新的理论基础。

Hepatic cholesterol metabolism is the key factor that affects the formation of cholesterol gallstone, and is a popular research topic in this field. In previous work, we found that osteopontin (OPN) could interfere with hepatic cholesterol metabolism by regulating the expression of cholesterol 7α-hydroxylase (CYP7A1), thus influencing cholesterol gallstone formation. However, the exact mechanism by which OPN regulates CYP7A1 expression needs to be further studied. CYP7A1 is the rate-limiting enzyme in hepatic cholesterol degradation. And CYP7A1 is regulated by PI3K/AKT, MEK/ERK and JNK at transcription level. OPN is an extracellular matrix protein, which needs to bind to integrin to activate downstream pathways thus performing biological functions. Focal adhesion kinase (FAK) is a key member to integrin transmitting signals. In preliminary experiment, FAK inhibitor can block the phenomenon that OPN down-regulates CYP7A1 expression in cell lines. Thus, we propose the hypothesis: OPN activates downstream pathways to down-regulate CYP7A1 expression through FAK, which further affects the formation of cholesterol gallstone. This study intends to clarify the exact mechanism by which OPN down-regulates CYP7A1 expression and affects cholesterol gallstone formation in cell lines, and to verify the mechanism in animal and human tissue. The results will further clarify the mechanism by which OPN affects the formation of cholesterol gallstone, and provide a new theoretical basis for the prevention and treatment of cholesterol gallstone.