宿主肝细胞内SEL1L基因对乙型肝炎病毒复制的调控机制以及miRNA-125b对SEL1L基因表达的表观遗传学修饰

The innate and adaptive immune response is thought to be responsible for viral clearance and disease pathogenesis during hepatitis B virus (HBV) infection. The mechanism of host genes effect on regulation of chronic HBV replication is unknown. From our previous study, the intrahepatic SEL1L levels have negative correlation with serum HBV DNA titers from 83 HBV-infected patients. In vivo experiment, silence of SEL1L with small interfering RNA could enhance HBV replication and over-express of SEL1L could suppress HBV replication significantly. In conclusion, SEL1L can inhibit HBV replication in hepG2.2.15 cell line. In addition, our previous study showed that miRNA-125b can enhance HBV replication and SEL1L is a potential target gene of miRNA-125b. Meanwhile，it is reported that activation of ERAD Pathway by HBV modulates viral and subviral particle production. So we have a hypothesis that miRNA-125b promote HBV replication through ERAD pathway suppression and SEL1L inhibition. This project is supposed to clarify the mechanism of SEL1L on control of HBV replication and regulation of miRNA-125b in hepatoma cell lines in vitro models and high-pressure tail vein injection mouse model. To verify whether the SEL1L could regulate the HBV replication via ERAD pathway and to clarify the miRNA-125b enhance HBV replication by its epigenetic modification on SEL1L. This study will help to identify the novel mechanism of micro RNA and ERAD pathway on HBV replication and to develop new insights on the HBV therapy.

慢性HBV感染患者肝细胞调控HBV复制的机制目前仍未阐明。本课题组前期研究发现，肝细胞SEL1L基因的表达水平与病毒载量呈负相关；在体外过表达和敲除SEL1L基因，可分别显著下调和上调HBV复制，而SEL1L基因是ERAD途径的重要功能基因；血清miRNA-125b水平与病毒载量呈显著正相关，而SEL1L是miRNA-125b的潜在靶基因。我们推测，miRNA-125b通过降低靶基因SEL1L的表达，抑制ERAD途径，从而促进HBV复制。我们拟在前期研究基础上，利用瞬转HBV细胞系、高压尾静脉注射HBV感染小鼠等模型，采用基因敲除或过表达、功能获得或缺失等方法，观察SEL1L基因是否通过ERAD途径调控HBV 复制，以及miRNA-125b是否通过对SEL1L基因的表观遗传学修饰而促进HBV复制。本研究有助于阐明宿主肝细胞基因调控HBV复制的机制，为寻找抗HBV的新靶位提供理论依据。

慢性 HBV 感染患者肝细胞调控 HBV 复制的机制目前仍未阐明。本课题组前期研究发现，肝细胞 SEL1L 基因的表达水平与病毒载量呈负相关;在体外过表达和敲除 SEL1L 基 因，可分别显著下调和上调 HBV 复制，而 SEL1L 基因是 ERAD 途径的重要功能基因。我们在后续研究中，进一步通过瞬转 HBV 细胞系、高压尾静脉注射 HBV 感染小鼠等模型，采用基因敲除或过表达、功能获得或缺失等方法，发现 SEL1L 基因可通过 ERAD 途径降解HBV包膜蛋白，并且可能通过另一ERQC-autophagy途径调控HBV复制。本研究有助于阐明宿主肝细胞基因调控 HBV 复制的机制，为寻找抗 HBV 的新靶位提供理论依据。