miR-1225-3p参与干扰素抗HCV的机制研究

Hepatitis C virus (HCV) infection and its related liver diseases are still serious threats to human health. miRNA, as an regulator of gene expression, has been proved to have an important antiviral effect. Interferon (IFN) is still a major component of hepatitis C treatment regimen. Research of IFN regulating miRNA to exert antiviral function is also less. Our previous study demonstrated that the down-regulation of miR-1225-3p was mediated by IFN and Significantly inhibited HCV infection, which illustrated that miR-1225-3p may be involved in the IFN-mediated anti-HCV process. There were no reports of miR-1225-3p features and effects. We propose to study the anti-HCV activity of miR-1225-3p and the molecular mechanism of IFN down-regulating miR-1225-3p expression. By miRNA target analysis, we will explore the mechanism of miR-1225-3p involving the antiviral process of interferon. This study will further expand our understanding of anti-HCV miRNAs and their antiviral mechanisms. Results from these studies will provide new clues and theoretical basis for the discovery of anti-HCV drugs of hepatitis C therapy.

丙型肝炎病毒（HCV）感染以及由此引发的各类肝病依然严重威胁着人类的健康。miRNA作为一类基因表达调控因子，已被证明在抗病毒方面具有重要作用。干扰素是丙型肝炎治疗方案的主要成分之一。干扰素通过调节miRNA来发挥抗病毒功能的研究还较少。我们前期研究发现：干扰素能够抑制miR-1225-3p的表达，而miR-1225-3p的低表达显著抑制HCV的感染，这提示miR-1225-3p可能参与了干扰素介导的抗HCV感染过程。目前还没有关于miR-1225-3p功能和特点的报道。本项目中我们拟对miR-1225-3p影响HCV感染的作用方式和干扰素下调miR-1225-3p的分子机理进行具体分析，并通过miRNA靶点分析，深入探究miR-1225-3p参与干扰素抗病毒的具体机制。上述研究将进一步拓展人们对miRNA抗HCV感染及机制的认识，为丙型肝炎治疗的抗病毒药物筛选提供新的线索和理论依据。

干扰素及其诱导产生是抗病毒天然免疫过程的关键环节。而microRNA（miRNA）作为重要的转录后调控因子，在干扰素抗病毒应答中发挥着重要的作用。人们已经发现干扰素能够调节相当数量的miRNA的表达水平，但是对这些miRNA在宿主抗病毒过程中发挥作用的具体机制缺乏细致描述。通过研究我们发现I型干扰素通过激活JAK-STAT信号通路，下调hsa-miR-1225-3p的表达水平。利用特异性miRNA抑制物降低内源miR-1225-3p水平后，丙型肝炎病毒（HCV）、仙台病毒（SeV）以及新城疫病毒（NDV）的感染受到抑制。利用生物信息学预测miR-1225-3p识别的宿主蛋白，鉴定并验证了GAB3（growth factor receptor-bound protein 2-associated binding protein 3）是miR-1225-3p的直接靶点之一。干扰素通过调节miR-1225-3p影响了miRNA的靶点GAB3的表达水平。GAB3的过表达能够显著增强宿主的天然免疫活化水平和干扰素应答水平，抑制病毒感染。我们的发现首次揭示了miR-1225-3p在天然免疫中的功能，并阐明了由miR-1225-3p和GAB3参与的抗病毒调节信号通路。本研究将有助于理解宿主miRNA参与干扰素抗病毒的过程，扩展了人们对干扰素调控的信号网络的认识，为干扰素抗病毒感染的临床应用具有一定指导意义。