CUG结合蛋白1在肝星状细胞持久活化及肝纤维化中的作用及其机制

Liver fibrogenesis is very complicated. Persistent activation of hepatic stellate cells (HSCs) plays a key role in liver fibrogenesis. However, the mechanism remains unclear. And there is still lack of biomarkers for diagnosing and treating liver fibrosis. Our previsous studies showed that expression of CUG binding protein 1 (CUGBP1) is correlated with the progress of liver fibrosis, and CUGBP1 enhanced TGF-β signaling, but inhibited IFN-γ expression. We propose a hypothesis that CUGBP1, a key factor in the crosstalk between TGF-β signaling and IFN-γ signaling, disrupts the balance, maintains the persistent activation of HSCs, and induces liver fibrosis. Here, we will determine the correlation between the expression of CUGBP1 and the progress of liver fibrosis using clinical and animal samples. We will investigate the cell population of high expressed CUGBP1 in fibrotic liver and the mechanism of inducing CUGBP1 expression in liver fibrosis tissue. We will determine the role of CUGBP1 in developing liver fibrosis in mice. Then, we will focus on the crosstalk between TGF-β signaling and IFN-γ signaling to clarify the mechanism of maintaining the perpetuation phase of HSC activation by CUGBP1. We will determine the molecular mechanism underlying the inhibition of IFN-γ expression by CUGBP1. This study would discover critical molecular events in liver fibrogenesis and provide fundamental knowledge for developing novel biomarkers, new strategies for the treatment of liver fibrosis.

肝纤维化成因复杂，其关键环节—肝星状细胞持久活化的机制迄今不明，诊断和治疗缺乏特异的生物标志物。前期研究发现临床肝纤维化样本中CUG结合蛋白1（CUGBP1）的表达与肝纤维化程度呈正相关，在肝星状细胞中CUGBP1可促进TGF-β信号却抑制IFN-γ信号。我们推测CUGBP1是TGF-β信号与IFN-γ信号对话的关键节点分子，通过扰乱信号平衡，使肝星状细胞持久活化，促进肝纤维化。为此，本项目借助临床及动物样本，确证CUGBP1表达与肝纤维化的相关性；明确其在肝组织中的细胞分布，探寻促进其高表达的诱因；在动物模型上探讨CUGBP1对肝纤维化的作用；围绕TGF-β信号与IFN-γ信号的对话，阐明CUGBP1维持肝星状细胞持久活化的机制；揭示CUGBP1抑制IFN-γ表达的分子机制。本项目可确立肝纤维化发生发展的关键分子事件，为建立新型生物标志物及开发肝纤维化相关疾病的新治疗方法奠定基础。

调控肝星状细胞是抗肝纤维化的关键，但缺乏合适切入点。本研究揭示了肝星状细胞中促纤维化信号和抗纤维化信号失衡的新机制，研究发现了肝星状细胞中CUG结合蛋白1（CUGBP1）的表达与肝纤维化程度呈正相关，阐明了活化肝星状细胞高表达CUGBP1的机制，即通过TGF-β-p38-ATF2信号促进CUGBP1的转录，而高表达的CUGBP1通过结合IFN-γ mRNA的3’UTR促进IFN-γ mRNA的降解，进而减弱IFN-γ信号对TGF-β信号的抑制。重要的是，靶向抑制CUGBP1可诱导活化肝星状细胞自分泌IFN-γ，进而恢复肝星状细胞稳态，改善小鼠肝纤维化。本研究首次发现了CUGBP1在促纤维化TGF-β信号与抗纤维化IFN-γ信号间的链接点样作用，为肝纤维化治疗提供了新策略及新靶标。