急性肾损伤(AKI)是导致肝移植不良预后和死亡的主要原因。我们前期研究首次发现Cx32组成缝隙连接(GJ)介导的“旁细胞效应”是AKI不断恶化的原因，但尚不清楚经何种途径发挥作用而影响后续临床开发。转录因子FoxO3a去乙酰化后核转位调控众多凋亡基因转录；我们经生物信息学分析发现AMPK/Sirt1活化对FoxO3a去乙酰化起重要作用；激活AMPK的AMP是通过GJ主要物质。据此我们设想：Cx32组成的GJ传递AMP激活AMPK/Sirt1/FoxO3a介导的细胞凋亡参与肝移植AKI。本项目是在前期工作基础上开展的延续性研究，拟用Cx32、Sirt1和FoxO3a基因敲除鼠、结合GJ抑制剂和激动剂、基因沉默和质粒转染等技术，通过动物肝移植模型和体外细胞学研究，阐明我们提出的假说，回答GJ传递信息引起肝移植AKI发生或恶化这一问题，完善AKI发生机制，为肝移植肾保护提供有效的靶标和理伦依据。

Acute kidney injury (AKI) following liver transplantation severely influences post-transplantational morality and morbidity in patients. We have found that the ‘bystander effect’ mediated by gap junction (GJ) composed of Cx32 deteriorated AKI continuously, but the mechanism remains unclear and effective therapy is lacking. FoxO3a is an important nuclear factor that regulates multiple genes which promote apoptosis through acetylation and translocation. Through analysis of bioinformatics, we noticed that the signal pathway of AMPK/Sirt1 contributed to FoxO3a acetylation. And more importantly, AMP (which activates AMPK) could be transferred through GJ. Our preliminary experiment indicated that liver transplantation induced significant increases in Sirt1 and FoxO3a activation which were concomitant with increased cell apoptosis, and inhibition of GJ composed of Cx32 could reverse this damage. We therefore hypothesized that apoptosis mediated by GJ composed of Cx32-triggerred Sirt1/FoxO3a activation participated in AKI following liver transplantation. This project is based on and is an advancement of our previous studies, and various methods will be used to verify our hypothesis. Studies will be performed in gene knockout mice of Cx32, Sirt1 and FoxO3a, in combination with the use of specific inhibitor of GJ, siRNA and palsmid transfection. Through our studies, we aim to provide new scientific basis for elucidating the mechanism of AKI after liver transplantation, and also offer a new potential target for its treatment.