RPA1在非酒精性脂肪性肝病中的作用及机制研究

非酒精性脂肪性肝病（NAFLD）是一种与胰岛素抵抗和遗传易感性密切相关的获得性代谢应激性肝损伤，是我国第一大慢性肝病，严重危害人民生命健康。然而，到目前为止，NAFLD的具体发病机制仍不明确。前期研究中，我们发现Rpa1基因敲除会导致小鼠发生NAFLD，且RPA1在NAFLD患者肝组织中表达水平也显著降低。RNA-Seq实验发现Rpa1敲除会引起小鼠肝脏脂肪酸代谢紊乱。本课题将在前期研究结果的基础上，利用RPA1敲除小鼠模型和高通量测序手段（ATAC-Seq、ChIP-Seq），明确RPA1调控脂肪酸代谢的分子机制。进一步本项目将利用公共数据库资源挖掘RPA1及上下游分子在大规模NAFLD临床队列肝组织中的表达水平，明确RPA1在NAFLD中的病生理学意义。本课题将阐明RPA1蛋白在肝脏中的全新生理功能，为NAFLD的诊断、预防以及创新药物研发提供新的思路和治疗靶点。

Non-alcoholic fatty liver disease (NAFLD) is an acquired metabolic stress-induced liver injury that is closely related to insulin resistance and genetic susceptibility. NAFLD is the largest chronic liver disease in China which seriously endangers people's health and wellbeing. However, the specific pathogenesis of NAFLD remains unclear currently. In our preliminary study, we found that Rpa1 knockout can induce NAFLD in mice. Furthermore, the RPA1 expression in livers of NAFLD patients were significantly reduced. We also found that Rpa1 knockout was related with the metabolism of fatty acid by using RNA-Seq. In the current study, we will learn the molecular mechanism of Rpa1 knockout induced NAFLD on Rpa1 knockout mouse. By High-Throughput sequencing assays such as ATAC-Seq and ChIP-Seq, we will clarify the molecular pathways that RPA1 involved in fatty acid metabolism. Finally, we will study the expression of RPA1 and related molecules in the liver of large-scale NAFLD clinical cohorts through public database to clarify the RPA1 related pathophysiology of NAFLD. In conclusion, the new physiological functions of RPA1 protein in the liver and how it involves in the pathogenesis of NAFLD will be explored in our study, providing theoretical basis of precision diagnosis and potential therapeutic targets for innovative drug development of NAFLD.