CD39-CD73-腺苷通路调控酒精性肝纤维化HSC活化增殖的作用及机制

肝纤维化是ALD进展的重要节点，HSC在酒精性肝纤维化形成中发挥重要作用。前期发现酒精性肝纤维化HSC腺苷A2AR和A1R激活后促进HSC活化增殖，证实腺苷信号参与酒精性肝纤维化的过程。我们推测以ATP和腺苷为主要信号分子的嘌呤信号通路在酒精性纤维化进程中至关重要，危险信号ATP的释放，以及CD39-CD73-腺苷通路的任一环节均可能潜在着干预HSC活化增殖的靶点，并与其预后密切相关。本课题拟建立酒精性肝纤维化小鼠模型，分离培养HSC，采用基因沉默、重组和CRISPR/Cas9敲除等技术，并结合不同嘌呤受体激动剂和拮抗剂，观察嘌呤信号通路相关分子在HSC中的表达及作用，研究CD39-CD73-腺苷通路调控HSC活化增殖的作用及发挥作用的主要环节。本课题将进一步阐明CD39-CD73-腺苷通路在酒精性肝纤维化发病机制中的作用，也为以嘌呤信号通路为靶点寻找酒精性肝纤维化的治疗途径提供新的思路。

Liver fibrosis is a key event of alcoholic liver disease, and HSC is a central mediator for alcoholic liver fibrosis (ALF). We previous found that activation of adenosine A2AR and A1R promoted the activation and proliferation of HSC in ALF, indicating that adenosine signaling is highly involved in the fibrogenesis of ALF. We presume that the purine signaling pathway, with ATP and adenosine as the major signaling molecules, plays a dominant role in the process of ALF. The release of ATP and CD39-CD73-adenosine signaling pathway, which are closely correlated with prognosis of ALF, may be potential targets for preventing the activation and proliferation of HSC. In this project, we plan to establish a mouse model of ALF and isolate the primary HSC, by using gene knockdown and recombination, CRISPR/Cas9-mediated gene knockout, and other techniques, in addition to different purine receptor agonists and antagonists, we try to detect the expression and function of purine signaling-related molecules while exploring the role and mechanism of CD39-CD73-adenosine pathway in HSCs. This study will further elucidate the role of CD39-CD73-adenosine pathway and provide a new therapeutic target for the treatment of ALF.