I 型干扰素负调控的分子机制及其在系统性红斑狼疮发病中的作用

I型干扰素在系统性红斑狼疮 (systemic lupus erythematosus, SLE) 发病中起关键作用。SLE患者典型的分子特征之一是I型干扰素高表达导致的下游信号通路异常激活和干扰素靶基因异常表达。由于过量干扰素对机体十分不利，机体需要通过各种负调控机制来严控干扰素产生。我们发现转录抑制因子hairy and enhancer of split 1 (Hes1) 能抑制Toll样受体诱导的I型干扰素表达，揭示了Hes1作为干扰素通路负调控因子的新功能。鉴于干扰素在SLE中的重要作用，Hes1很可能也参与了SLE的发病过程。但Hes1调控I型干扰素的分子机制和其在SLE中的具体作用尚不清楚。本项目将深入研究Hes1 调控干扰素产生的分子机制，并探索Hes1在SLE动物模型中的作用。本研究将有助于揭示SLE中干扰素的负调控机制，为SLE等自身免疫病的治疗提供新型药物作用靶点。

One of the prominent immunological abnormalities closely associated with SLE is upregulation of type I interferons (IFNs). Molecular and cellular mechanisms that lead to excessive production of type I IFNs in SLE has been a subject under extensive investigation and the research effort has focused on identifying factors and pathways that positively regulate IFNs expression. On the other hand, given their potential harmful effects, production of type I IFNs is under tight control by various inhibitory mechanisms that prevent over-activation of this pathway. We postulated that besides abnormal activation of positive IFN-inducing pathways, dysregulation of homeostatic inhibitory mechanisms also contributes to excessive IFN production seen in SLE and identified transcription repressor hairy and enhancer of split 1 (Hes1) as a previously unappreciated negative regulator of IFN expression. In this application, we propose to investigate the molecular mechanisms by which Hes1 inhibits the type I IFN pathway as well as the in vivo significance of Hes1 regulation of IFNs in animal models of SLE. The proposed study will contribute to our understanding of IFN regulation in the context of SLE pathogenesis and shed light on designing novel therapeutic approaches targeting type I IFNs.