抑制SIK1易化蓝光牵引重置SCN生物钟逆转吸入全麻药致小鼠昼夜节律紊乱研究

正常昼夜节律对全身各器官系统正常功能至关重要。全球每年3亿手术患者中75%需要全身麻醉，吸入性全麻药使用方便且广泛。我们前期研究证实吸入性全麻药可引起小鼠昼夜节律严重紊乱，表现为活动能力变化，褪黑素昼夜节律消失。哺乳动物生物钟“中枢起搏点”位于视交叉上核。吸入性全麻药可引起钟基因相位偏移/表达量降低，机制可能与吸入性全麻药影响mPer基因转录启动过程或改变钟基因调控相关蛋白激酶GSK3β和AMPK磷酸化水平有关。本研究利用短波长光能有效牵引视交叉上核生物钟重置的天然现象，在小鼠麻醉前或苏醒后启动蓝色光照（480nm）前处理或后处理，同时抑制光牵引自限性关键酶SIK1，易化日常照度条件（800lux）光牵引效果，以期逆转或对抗吸入麻醉药诱发的小鼠视交叉上核生物钟紊乱，恢复全麻后正常昼夜节律。并探索光牵引逆转效果的关键分子机制，为临床防治吸入性全麻药诱发昼夜节律紊乱及其相关不良反应提供策略。

The normal circadian rhythm is critical for the normal physiological functions of all organs in the body. General anesthesia is required for 75% of the 300 million surgical patients worldwide each year, for which inhalational anesthetics are the most convenient and widely used. Our previous study confirmed that inhalational anesthetics can cause severe circadian disorders, manifested as changes of motor activity and loss of melatonin circadian rhythm. The "central pacemaker” of circadian clock in mammalian located in the suprachiasmatic nucleus (SCN). Inhalational anesthetics can cause phase shifting and decreasing of clock gene expression in SCN. The mechanism may be related to perturbation of transcription onset of mPer gene and changes in phosphorylation level of GSK3β and AMPK that involved in the regulation of clock gene. This study aims to reset circadian clock in SCN by the use of naturally existed light entrainment phenomenon especially with short wavelength blue light. Blue light preconditioning or postconditioning will be given to mice before or after anesthesia. Meanwhile we design to inhibit the light entrainment limitation enzyme SIK1, to facilitate light entrained circadian clock reset under normal illumination level (800lux), so as to reverse or against inhalational anesthetics induced SCN circadian disorder in mice, and to restore the normal circadian rhythm after anesthesia. We will also explore the key molecular mechanisms that mediate reversing effects of blue light preconditioning or postconditioning in combination with SIK1 inhibitor, so as to develop innovative strategies for prevention and treatment of circadian disorder and the related adverse reactions following use of inhalational anesthetics in clinical setting.