LncRNA -NORAD 通过SRSF1蛋白参与APAP诱导的急性肝损伤中肝细胞修复的作用及机制研究

Drug-induced liver injury is a common adverse drug reaction, which can cause liver failure. Up to now, the clinical treatment effect for acute liver injury is unsatisfactory. Recent studies have shown that LncRNA NORAD plays an important role in genomic stability and cell proliferation, but its function in acute liver injury has not been reported. Our preliminary results showed that LncRNA NORAD expression was significantly upregulated in APAP-treated hepatocyte injury models, which suggested that LncRNA NORAD may play a role in acute liver injury. Combing literature report and online database results showed that LncRNA NORAD could bind to SRSF1 protein, which may lead to enhancement of SRSF1 function. It has been reported that SRSF1 activate Wnt/β-catenin signal pathway, and promote the translation of β-catenin targeted genes. Accordingly, we hypothesized that in the process of acute liver injury, LncRNA NORAD, by interacting with SRSF1 protein, regulates the Wnt/β-catenin signal pathway and affects the function of hepatocyte.

药物性肝损伤是一种常见的药品不良反应，严重者可致肝衰竭。目前，临床对于急性肝损伤干预治疗效果仍然不满意。近期研究显示，LncRNA NORAD在基因组的稳定性和促进细胞的增殖中发挥重要作用，但其在急性肝损伤中的作用机制尚未见研究报道。我们前期预实验结果显示，在APAP处理的肝细胞损伤模型中，LncRNA NORAD表达显著上调, 提示LncRNA NORAD可能在急性肝损伤过程中发挥作用。我们前期查阅文献并利用在线数据库预测结果都发现：LncRNA NORAD可以与SRSF1蛋白相互作用，其可能参与调控SRSF1的功能。文献报道，SRSF1可促进其结合的β-catenin mRNA翻译。因此，我们提出以下科学假说：在急性肝损伤过程中，LncRNA NORAD通过与SRSF1蛋白相互作用，激活下游Wnt/β-catenin信号通路，参与急性肝损伤中肝细胞的修复。

肝细胞是肝脏的主要功能细胞，易受药物和酒精等毒性物质、自身免疫、代谢异常等致病因素的影响，引起肝脏损伤。对乙酰氨基酚(acetaminophen，APAP)是临床常用的非甾体类解热镇痛药，大剂量应用或某些特殊情况下服用会引起肝细胞坏死，引起急性肝损伤。依据项目计划，我们通过RNA-seq转录组学揭示了APAP诱导急性肝损伤的差异基因及关键信号通路；LncRNA NORAD在急性肝损伤的早期表达升高，随着损伤加重表达下降，提示其表达与急性药物性肝损伤的进展有关；进一步干扰和过表达实验，明确LncRNA NORAD在急性肝损伤中的作用，过表达LncRNA NORAD可以缓解急性肝损伤。另外，基于肝脏损伤疾病研究的总体方向，我们还探究了胆汁淤积性肝损伤的分子机制，发现了遗传性胆汁淤积性肝病ABCB11 基因新的异常致病变异，并进行了功能性的挽救实验。本课题主要围绕肝损伤发生发展的病理生理机制开展研究，探讨新的分子机制，为肝脏损伤疾病提供新的临床思路和治疗靶点。