细胞衰老导致器官功能低下并抑制再生。研究证明强烈的急性应激能诱导细胞早衰，且衰老可向周围细胞扩散而放大；近年发现肝缺血再灌注损伤（HIRI）后出现细胞衰老，但其作用和传播途径不明。我们前期研究证明Cx32组成缝隙连接（GJ）介导的“旁细胞效应”能放大HIRI，与GJ传递活性氧（ROS）有关。预实验显示抑制GJ功能减少细胞衰老并减轻肝损伤。P53/p21是衰老最重要触发器；生物信息学分析显示激活衰老相关p53上游信号酶为ATM激酶；ROS能激活ATM并经GJ传递；据此我们设想“Cx32组成的GJ传递ROS激活ATM/p53/p21促进细胞衰老和扩散参与HIRI”。拟用野生型和Cx32-/-小鼠HIRI模型及细胞缺氧复氧模型，结合GJ工具药和基因过表达和沉默等技术，检测肝损伤、细胞衰老、GJ功能、相关蛋白改变等，从全新视角来阐明HIRI机制，为以预防细胞衰老减轻HIRI提供理论依据和干预靶点。

Cellular senescence leads to organ dysfunction and failed regeneration.Strong acute stress has been demonstrated to induce premature senescence,in addition,senescent cells can induce senescence in surroungding cells,which contributes to the spread of aging.Recently,stress-induced premature senescence was found in liver following ischemia/reperfusion(I/R),but the effect and spread mechanism remain largely unclear.Our previous study demonstrated gap junction(GJ) composed of Cx32-mediated”bystander effect”could amplify hepatic I/R injury,which was related to GJ mediated ROS intercellular transfer.Our preliminary study showed that inhibition of Cx32 attenuate senescence and senescence-related proteins expression,ultimately relieve liver injury.P53/p21 pathway plays a key role in aging.Through analysis of bioformatics,we noticed that ATM kinase is the upstream signal enzyme of p53.ROS is GJ-permeateable substance which is also the activator of ATM kinase.We therefore hypothesized that Cx32-gap junction transmitted ROS-induced cell senescence mediated by ATM/p53/p21 activation contributes to hepatic ischemia/reperfusion injury. Studies will focus on cellular senescence and be performed in wild and Cx32-/- mice,in combination with the application of specific inhibitor of GJ, gene silencing and overexpression techniques,to explore the effect and molecular mechanism of Cx32-mediated cellular senescence during hepatic I/R injury and provide new potential target for its treatment.