生物节律主导机体的日夜活动、代谢需求、能量分配等多个重要过程。节律紊乱常伴随衰老过程发生，并且是导致代谢疾病、睡眠障碍及神经退行性疾病的重要原因之一。虽然已有大量的研究阐明了生物节律核心基因的功能及其调节机制，然而干预节律紊乱的有效手段仍十分缺乏。本项目拟结合前期抗衰老蛋白SIRT1参与中枢节律调节的发现，进一步探讨其它细胞核内Sirtuin在节律调控中的作用。通过评估SIRT6及SIRT7对细胞生物钟活性的调节，对节律中枢活性的影响，并结合小鼠节律行为分析，本项目将系统研究不同Sirtuin对生物节律的影响效率，以及对中枢生物钟的维持作用。本工作也将分析老龄小鼠的视叉上核表达谱和蛋白修饰改变，寻找导致节律衰退的关键基因或蛋白变化，进一步了解Sirtuin在视叉上核及其他相关下丘脑核团衰退的关联。此研究结果将有助于了解生物节律的衰退过程，并为节律紊乱的临床治疗提供更深入的基础与潜在的靶点。

Circadian rhythm governs the vital processes of daily activities, metabolic requirements and energy expenditures in essentially all living organisms. Circadian disorder often associates with aging progression, and is considered to be a main cause for metabolic diseases, sleep disorders and neurodegenerative diseases. Despite the vast knowledge on core circadian gene functions and their regulatory roles, effective intervention for circadian disorders remains scarce. Based on our earlier finding of longevity-mediating SIRT1 in central circadian modulation, we propose to further investigate other nuclear Sirtuins for their potential roles in circadian regulation. We plan to examine the effects of SIRT6 and SIRT7 in circadian gene regulation in vitro and their impacts on suprachiasmatic nucleus (SCN) activity. We will also perform a series of circadian behavior analyses to justify Sirtuin function in vivo. The outcomes will elucidate the efficiencies of different Sirtuins in circadian regulation, and their capabilities to sustain rhythmic, functional central clock. We will also inspect aged animals for the SCN transcriptomes and post-translational modifications to reveal landmark changes in explaining age-related circadian decay. The results will further connect Sirtuin activities to the prevention of SCN degeneration, and perhaps are applicable to subsidiary circadian hypothalamic nuclei as well. The study will shed light on the nature of circadian decay, and may provide deeper understandings for circadian disorder thus in turn advocate perspective targets.