LncRNA-uc008xkb.1调控PGC-1α介导肝脏缺血再灌注损伤的机制研究

Liver ischemia-reperfusion injury（LIRI）usually occurs in liver transplantation, trauma, shock and elective liver resection when inflow occlusion or total vascular exclusion is used to minimize bleeding, and it may contribute to morbidity and mortality during these events. Therefore, many efforts have been put into this area, but the precise mechanisms responsible for LIRI are still not well understood. In recent years,growing evidence demonstrates that long noncoding RNA (LncRNA) plays important regulatory roles in many physiological processes. Our previous studies showed that the expression level of lncRNA-uc008xkb.1 was decreased during LIRI. Hepatocytes overexpressing lncRNA-uc008xkb.1 were more sensitive to oxidative stress injury. The further bioinformatics prediction and western blot assay showed that PGC-1α, one of its nearby genes, might be a potential key target of it. However, PGC-1α has been proven to be a key protective target during LIRI in our previous study. Therefore, we hypothesize that lncRNA-uc008xkb.1 mediates LIRI via regulating the expression of PGC-1α. This study intends to certify that lncRNA-uc008xkb.1 may aggravate the extent of LIRI in vitro and in vivo，then investigates the molecular mechanisms behind this process.

肝脏缺血再灌注损伤（LIRI）多发生于肝脏外科手术中，是影响肝移植、肝切除术后肝功能的重要因素，现已成为肝脏外科领域的研究热点，但其具体机制迄今尚未完全阐明。新近研究表明，长链非编码RNA(lncRNA）广泛参与机体各项生理病理过程并发挥重要调控作用。我们前期研究发现，lncRNA-uc008xkb.1在LIRI过程中表达显著下调，上调肝细胞uc008xkb.1的表达可加重氧化应激损伤。后续的生物信息学及蛋白质电泳分析表明其邻近的PGC-1α编码基因可能是潜在作用位点，而PGC-1α为本课题组前期原创性鉴定的LIRI过程中重要调控靶点。因此，我们提出假说：lncRNA-uc008xkb.1通过调控PGC-1α介导LIRI。本项目拟通过体内外实验对该假说加以验证，进而从lncRNA的角度深入探究LIRI的损伤机制，为LIRI的损伤评估提供新的检测指标，同时也可为其防治提供新的干预靶点和举措。

肝脏缺血再灌注损伤（LIRI）多发生于肝脏外科手术中，是影响肝移植、肝切除术后肝功能的重要因素，现已成为肝脏外科领域的研究热点，但其具体机制迄今尚未完全阐明。新近研究表明，长链非编码RNA(lncRNA）广泛参与机体各项生理病理过程并发挥重要调控作用。我们前期研究发现，lncRNA-uc008xkb.1在LIRI过程中表达显著下调，上调肝细胞uc008xkb.1的表达可加重氧化应激损伤。后续的生物信息学及蛋白质电泳分析表明其邻近的PGC-1α编码基因可能是潜在作用位点，而PGC-1α为本课题组前期原创性鉴定的LIRI过程中重要调控靶点。因此，课题组认为lncRNA-uc008xkb.1通过调控PGC-1α介导LIRI。本项目进一步研究表明，lnc-uc008xkb.1的序列完全包含在了PGC-1α的序列里，但在非CDS区域，目前检测手段无法将两者完全区分，因此将lnc-uc008xkb.1移出LncRNA数据库。课题组进一步研究确定了调控PGC-1α的LncRNA为HNF-4aos，具体通路为HNF-4aos---HNF-4a---mircroRNA-23a---PGC-1α，研究成果对于解释LIRI的损伤机制具有重要的理论意义。