肝实质细胞的药物代谢功能成熟依赖ECM的调节作用，但机制并不清楚。我们研究发现，整合素α5β1-Src信号轴介导ECM信号，促进人脂肪干细胞分化的肝实质样细胞中核受体PXR的表达及CYP450酶活性。敲减整合素α5可降低参与基因启动子DNA去甲基化的蛋白Tet1和Tet3的mRNA水平。因PXR的低表达与其启动子DNA高甲基化密切相关，由此推测，整合素α5β1-Src信号轴通过促进PXR启动子DNA的去甲基化，上调PXR的表达，促进肝实质细胞药物代谢功能的成熟。本研究拟利用定量PCR、MeDIP-qPCR、ChIP-qPCR、蛋白印迹和P450-Glo分析等方法，研究人肝实质细胞及肝实质细胞特异性敲除整合素α5小鼠中，整合素α5β1-Src信号轴对Tet及Src下游转录因子c-Jun表达的调节作用，明确Tet及c-Jun与PXR启动子DNA去甲基化、PXR的表达和CYP450酶活性的关系。

The drug metabolic functional maturation of hepatocyte is dependent on the regulation of extracellular matrix. However, the regulatory mechanism of extracellular matrix in this process is not very clear. Result in our previous studies shown that the expression of PXR and the activities of CYP450 in human adipose stem cell-derived hepatocyte-like cells (hASC-HLCs) were regulated by the integrin α5β1-src signal axis. Reducing the expression of α5 integrin decreased the ten-eleven translocation (Tet) family of dioxygenases 1 and Tet3 mRNA levels, which responsible for the demethylation of gene promoters. Studies have suggested that the DNA methylation of the PXR promoter was more densely detected in the PXR low expression cells. We wondered whether the expression of PXR regulated by the α5β1-Src signal axis is dependent on the DNA demethylation of the PXR promoter, which promoted the expression of nuclear receptor PXR and resulted in the metabolic functional maturation of hepatocyte. In this study, the regulation of the α5β1-Src signal axis on the expression of tet protein and the transcription factor c-Jun, the key transcription factor in Src signal pathway, the regulation of tet protein and c-Jun on the DNA demethylation of the PXR promoter, the expression of PXR and the CYP450 activities will be explored in the hASC-HLCs and human hepatocyte in vitro and the hepatic specific integrin α5 knock out mice in vivo using real-time RT-PCR, MeDIP-qPCR, ChIP-qPCR,western blot and P450-Glo assay.