PKCβ2/Nox2信号介导的氧化还原节律紊乱在睡眠剥夺诱导的认知功能损害中的作用机制研究

Sleep disorders cause dysfunctional cognition extremely easily, which is related to the destruction of redox homeostasis and circadian rhythms. Recent studies found that cellular redox state is rhythmical, and PKCβ2/Nox2 signaling pathway play a significant role in the regulation of redox state. Our previous study found that inhibition of PKCβ2/Nox2 signaling overactivation induced by sleep deprivation can significantly ameliorate hippocampal oxidative stress injury and improve cognitive function in rats. Further studies showed that BMAL1 (circadian rhythms gene) knockdown results redox rhythm disorder and susceptibility to oxidative stress injury in primary hippocampal neurons. However, antioxidants treatment effectively inhibited the diurnal hydrogen peroxide exposure induced downregulation of Bmal1 and PKCβ2/Nox2 signal hyperactivation. Therefore, we hypothesize that PKCβ2/Nox2 signaling pathway mediated sleep deprivation-induced cognitive dysfunction via perturbing redox rhythm. In the current proposal, we will construct acute sleep deprivation model and primary hippocampal neuronal hydrogen peroxide damage model, incorporating the use of specific inhibitor, shRNA gene technology, antioxidants, to elucidate the role and mechanism of PKCβ2/Nox2 signaling pathway and redox rhythm in sleep deprivation-induced cognitive dysfunction. This proposed study will improve our understandings of sleep and cognition and may help facilitate the development of novel and optimal therapies in sleep disorder and cognition degeneration.

睡眠紊乱极易导致认知功能损害，其机制与氧化还原稳态破坏及生物钟节律紊乱有关。新近研究发现氧化还原稳态具有节律性，而PKCβ2/Nox2信号通路是机体调控氧化还原稳态的重要机制。我们前期研究发现，抑制睡眠剥夺诱导的PKCβ2/Nox2信号过度活化，可显著减轻海马氧化应激损伤，有效改善大鼠认知功能。进一步研究发现，沉默节律基因BMAL1可导致原代海马神经元氧化还原节律消失，且氧化应激损伤易感性增加；而抗氧化剂可有效抑制日间过氧化氢曝露诱导的Bmal1表达下调和PKCβ2/Nox2信号活化。据此，申请者推测：PKCβ2/Nox2信号通路介导的氧化还原节律紊乱是睡眠剥夺诱导认知功能损害的重要机制。本项目拟构建急性全睡眠剥夺模型和原代海马神经元过氧化氢损伤模型，应用特异性抑制剂干预、shRNA基因沉默技术、抗氧化治疗，旨在阐明氧化还原节律在睡眠与认知中的潜在作用及PKCβ2/Nox2信号的调控机制。

睡眠紊乱极易导致认知功能损害，其机制与氧化还原稳态破坏及生物钟节律紊乱有关。新近研究发现氧化还原稳态具有节律性，而PKCβ2/Nox2信号通路是机体调控氧化还原稳态的重要机制。我们前期研究发现，抑制睡眠剥夺诱导的PKCβ2/Nox2信号过度活化，可显著减轻海马氧化应激损伤，有效改善大鼠认知功能。进一步研究发现，沉默节律基因BMAL1可导致原代海马神经元氧化还原节律消失，且氧化应激损伤易感性增加；而抗氧化剂可有效抑制日间过氧化氢曝露诱导的Bmal1表达下调和PKCβ2/Nox2信号活化。据此，申请者推测：PKCβ2/Nox2信号通路介导的氧化还原节律紊乱是睡眠剥夺诱导认知功能损害的重要机制。本项目构建了急性全睡眠剥夺模型和原代海马神经元过氧化氢损伤模型，应用特异性抑制剂干预、shRNA基因沉默技术、抗氧化治疗，阐明氧化还原节律在睡眠与认知中的潜在作用及PKCβ2/Nox2信号的调控机制.