沉默TLR信号通路分子TAB2抑制HBV复制的机制研究

The chronic liver diseases caused by hepatitis B virus (HBV）infection remain major health burden. The inhibition of HBV replication and gene expression by Toll like receptor (TLR)-mediated innate immune responses has been demonstrated by several studies. However, the molecular pathway of intracellular antiviral mechanism remains unclear. From our previous studies, the ligands of TLR2 could inhibit HBV replication in hepatocytes through activation of intracellular signal pathways, such as NF-kB, PI3K/Akt and MAPKs. By use of siRNAs screening TLR2 pathway proteins, we found that knock down of transforming growth factor-β-activated kinase 1 binding protein 2 (TAB2) resulted in significant inhibition of HBV replication and gene expression. And this was associated with reduction of activity of HBV gene promoters. Hence, we speculated that TAB2 might modulate HBV replication and gene expression in hepatocytes. The current project supposed to verify the antiviral effect on HBV replication by knock down of TAB2 in hepatoma cell lines in vitro and in hydrodynamic tail vein injection mouse model in vivo. Meanwhile, we will investigate the possible mechanisms. Furthermore, We will explore whether knock down of TAB2 could enhance the antiviral activity of TLR2 ligand on HBV replication. This study will be helpful to clarify the molecular mechanism of TLR-mediated anti-HBV response and provide experimental and theoretical evidences for searching new molecular target in therapy of chronic hepatitis B.

乙型肝炎病毒（HBV）感染所致慢性肝病危害严重。Toll样受体（TLR）介导的抗HBV效应已在多种体内外模型中得到证明，但其胞内抗病毒机制尚不明确。本课题组前期研究表明TLR2配体在肝细胞内通过激活NF-kB、PI3K/Akt和MAPKs信号通路，有效地抑制HBV的复制。进一步利用siRNA沉默TLR2通路蛋白发现，降低转化生长因子激酶1结合蛋白2（TAB2）表达后显著抑制HBV 复制和抗原表达，伴随HBV基因启动子转录活性的降低。由此我们推测，TAB2参与肝细胞内HBV 复制及基因表达的调控。本课题拟在肝癌细胞系体外模型和高压尾静脉注射的小鼠模型中，进一步验证沉默TAB2对HBV复制的抑制效应，同时阐明其作用机制，并将探讨沉默TAB2是否可以增强TLR2配体的抗HBV效应。本研究有助于阐明TLR信号通路调控HBV复制的胞内分子机制，为寻找新的慢性乙肝治疗的分子靶点提供理论和实验依据。