RIG-I影响慢性乙型肝炎患者IFN-α疗效机制研究

Retinoic acid-inducible gene I (RIG-I) is one of the most important pattern recognition receptors (PRRs), and it has attracted much attention since it can recognize various virus and is related to the development and progression of many diseases. However, the relationship between RIG-I and the treatment response of IFN-α in chronic hepatitis B (CHB) remains largely unknown. Our pre-experiment showed there is some correlative relationship between RIG-I and the treatment response of IFN-α. Therefore, we take immune regulatory and immune network as key point and hypothesize that RIG-I level is related to the treatment response of IFN-α. To test the above hypothesis and to explore the potential mechanism, we will concentrate on RIG-I and its regulatory role in the antiviral proteins in IFN signaling pathway. Firstly we will investigate the relationship between RIG-I and the treatment response of IFN-α in patients with chronic hepatitis B, then we will explore the biological function of RIG-I from the gene, protein and cell level via multiple ways including real time PCR, western-blot and RNA interference, etc. .Our research is expected to provide new ideas for searching new diagnostic markers associated with treatment differences of IFN-α in CHB, and to provide experimental basis for the implementation of individual treatment of CHB. Therefore, our research is of important theoretical and practical significance.

维甲酸诱导基因I（RIG-I）是重要的模式识别受体（PRRs）之一，因识别病毒种类多、与多种疾病发生发展有关而备受关注，但RIG-I与慢性乙型肝炎（CHB）患者IFN-α疗效的关系未明。我们前期预实验结果提示RIG-I与IFN-α疗效有一定的相关，为此我们以免疫调控和免疫网络为切入点，提出“RIG-I水平与IFN-α疗效差异有关”的假说。为了验证这一假说及探讨可能存在的机制，我们将以RIG-I及其对IFN通路下游抗病毒蛋白表达的调控为研究主线，首先探讨RIG-I与CHB患者IFN-α疗效的关系，其次采用Real time PCR、Western-blot、慢病毒载体转染、RNA干扰等手段，从基因、蛋白水平等多方面深入研究RIG-I生物学功能。.本研究理论上可为寻找新的IFN-α疗效预测诊断标志物提供思路和奠定理论基础；实践中有望为CHB患者实施个体化诊疗提供依据，有重要的理论和实际意义。

视黄酸（维甲酸）诱导基因蛋白1（Retinoic acid-Inducible Gene I, RIG-I）一方面通过诱导肝细胞分泌干扰素（Interferon, IFN），刺激机体免疫系统产生抗病毒应答；另一方面通过与HBV聚合酶竞争HBV前基因组 RNA 的 5’末端，从而干扰 HBV复制。本研究探讨了慢性乙型肝炎（Chronic hepatitis B, CHB）患者RIG-I表达与IFN疗效的关系；评价了临床常用指标（如HBsAg、HBV DNA）及RIG-I表达量对CHB患者IFN疗效的预测价值；本研究通过一系列的细胞学实验，初步揭示了RIG-I导致IFN疗效差异可能的机制。结果发现RIG-I表达影响CHB患者IFN疗效，RIG-I表达量高，IFN疗效好。与传统检验指标相比，RIG-I预测CHB患者IFN疗效的特异性及敏感性均较HBsAg及HBV DNA高，其可作为新的预测CHB患者IFN疗效指标。RIG-I通过正向作用于JAK-STAT信号通路，促进ADAR1、MxA、PKR、OAS等抗病毒蛋白的表达，从而增强IFN抗病毒的疗效。.本研究理论上可为寻找新的IFN疗效预测诊断标志物提供思路和奠定理论基础；实践中有望为CHB患者实施个体化诊疗提供依据，有重要的理论和实际意义。