巨噬细胞YAP蛋白通过NRF2/HIF1α通路对肝脏缺血再灌注损伤的保护作用及机制研究

肝脏移植是终末期肝脏疾病最为有效的治疗手段之一，但移植中缺血再灌注损伤（IRI）严重影响其临床疗效。已证实肝脏巨噬细胞（KCs）活化是IRI氧化应激和炎症损伤的主要原因。YAP是新近发现的对KCs活化起着重要调控作用的蛋白。我们前期研究证实YAP通路能够负向调节肝脏氧化应激反应。进一步实验发现通过诱导YAP能够增强氧化应激因子HIF1α的活化，并且在NRF2敲除小鼠模型中YAP无法逆转肝脏缺氧损伤。而肿瘤方面研究已证实NRF2下游分子NQO1能够结合并活化HIF1α。据此我们提出假说:KCs缺氧应激时YAP分子激活，通过NRF2依赖性途径由其下游NQO1调控HIF1α的活化，从而减轻组织损伤。本项目拟在前期研究基础上，以YAP对缺氧应激关键因子HIF1α活化的调控为切入点，探寻肝脏巨噬细胞YAP/NRF2/HIF1α通路可能的作用机制，为减轻肝脏IRI提供新的理论依据和临床治疗策略。

Ischemia-reperfusion injury（IRI）seriously affects the clinical outcome of liver transplantation, with the activation of liver macrophages (KCs) being the main cause of oxidative stress response and inflammatory injury. Yes associated protein（YAP）plays an important regulatory role in the activation of liver macrophages. Our previous clinical studies on liver transplantation have demonstrated the YAP pathway can negatively regulate the oxidative stress response in liver, but the specific mechanism remains to be eluciated. In the preliminary experiment, we found inducing YAP could enhance the activation of oxidative stress factor Hypoxia-inducible factor 1α（HIF1α）, and further studies found that the activation of YAP in nuclear factor E2-related factor 2（NRF2） knockout mice could not reverse the liver hypoxic injury. Oncology studies have demonstrated that NADH Dehydrogenase, Quinone 1（NQO1）, a downstream molecule of NRF2, could induce HIF1α activation by structurally binding to it. Based on these findings, we hypothesized that the activation of YAP in hypoxic stress, leading to HIF1α negatively induction by NRF2-dependent pathway downstream NQO1, result in reduction of liver tissue damage.Based on previous clinical and animal studies, this project intends to explore the possible mechanism of the liver macrophage YAP/NRF2/HIF1α pathway through the activation and regulation of the key factor HIF1α, in order to provide a new theoretical basis and strategy for the clinical alleviation of liver IRI.