生物钟调控在紫檀芪改善短期睡眠限制小鼠肝脏糖脂代谢中的作用及机制研究

睡眠限制（SR）是代谢综合征发生的独立危险因素。最新研究表明，生物钟介导的代谢调控扰乱及其后续效应是短期SR所致可逆性代谢紊乱进展为代谢性疾病的根本原因。我们前期研究发现，紫檀芪可提高SR小鼠耐力和维持骨骼肌核心钟基因节律，提示紫檀芪可能通过调控生物钟参与代谢调节。本项目拟采用小鼠短期SR模型证实紫檀芪的代谢改善作用，并结合基因芯片、乙酰化修饰组学等技术对核心钟基因敲除和野生型小鼠肝脏核心钟基因、代谢相关钟控基因转录表达及乙酰化水平及昼夜节律进行分析，以揭示其在生物钟介导的转录及翻译后修饰水平上的调控作用；研究进一步采用基因敲减、荧光素酶报告基因及活体成像技术，从调节Rev-erb/ROR-BMAL1反馈回路和影响NAD+依赖去乙酰化酶Sirtuins活性两方面，在体内外深入探讨紫檀芪参与生物钟调控的分子机制。本项目从时间生物学角度揭示紫檀芪代谢调节机制，将为其开发利用提供科学依据。

Sleep restriction (SR) is an independent risk factor for the development of metabolic syndrome. Recent studies have shown that the disruption of clock-mediated metabolic regulation and its long-term aftereffects might be the main cause of the progression of reversible metabolic disorders caused by short-term SR to metabolic diseases. Our previous study found that pterostilbene (PTE) can improve the endurance of SR mice and is related to the maintenance of skeletal muscle core clock gene rhythm, suggesting that PTE may participate in metabolic regulation via the biological clock machinery system. In this project, the short-term SR model of mice will be used to verify the improvement effect of pterostilbene on metabolic disorders. Meanwhile, combined with the advanced technology including the gene microassay and acetylome, the transcriptional and post-translational acetylation rythmn of the core clock gene and the metabolic-related clock-controlled genes in both the clock gene deficiency mice and the wild-type mice will be analyzed to reveal whether the mitagation effect of PTE is clock-dependent. In order to clarify the molecular mechanisms, using siRNA, luciferase reporter gene analysis and molecular imaging in vivo technology, further investigations will focus on whether the clock-mediated regulations iare associated with the modificaiton of the activation status of the Rev-erb/ROR-BMAL1 pathway and the activity of the NAD+-dependent deactylation enzyme Sirtuins.This project will elucidate the metabolic regulation mechanism of PTE in the circadian biology perspective, which would support scientific evidences for better use the PTE.