从SIRT1/BMAL1/NAD+信号通路探讨交泰丸改善绝经后女性睡眠障碍和NAFLD双重功效的共同分子机制

交泰丸由黄连、肉桂组成，是绝经前后妇女不寐证的常用方。前期研究显示，交泰丸既能改善中年女性睡眠障碍又能改善其脂肪肝，但具体机制不明。新近发现，中老年女性睡眠障碍破坏能量稳态妨碍健康衰老。本课题以衰老与生物钟-能量代谢：绝经后女性改善睡眠障碍、防治NAFLD的命运共同体为切入点，提出“调控SIRT1/BMAL1/NAD+通路：交泰丸改善绝经后女性睡眠障碍和NAFLD的共同分子机制”的假说，建立中老年绝经慢性不完全性睡眠剥夺肝脏脂肪变性雌性大鼠模型，在睡眠描记和检测脂代谢、性激素昼夜水平及受体表达的同时，采用RT-PCR、Western-blot、HPLC等方法，检测下丘脑和肝组织抗衰老蛋白SIRT1、生物钟蛋白BMAL1基因表达的变化，及肝组织NAD+相关能量代谢通路分子的活性和表达，探讨交泰丸作为SIRT1激活剂的可能性，促生一种基于抗衰老、调节生物钟，服务于绝经后女性脂肪肝的治疗新方法。

Jiao-tai-wan, a classic Chinese herbal formula, contains Rhizoma Coptidis and Cinnamon, has been widely used to treat insomnia of peri- and post-menopausal women in China. Previous evidence has demonstrated the dual efficacy of Jiao-tai-wan at improving sleep disorders and fatty liver of middle-aged women, for which the precise mechanism remains unclear. Recent researches have shown that the healthy aging and metabolic homeostasis of middle and aged women depends on sleep health. Given that aging and circadian rhythm-liver metabolism contribute to the development of sleep disorders and NAFLD of postmenopausal women, we hypothesize that Jiao-tai-wan concurrently improve sleep disorders and NAFLD of postmenopausal women through regulating the SIRT1/BMAL1/NAD+ signaling pathway. To test our hypothesis, we will establish animal models of chronic partial sleep deprivation in postmenopausal/ageing female rats in which hepatic tissue is steatosis and anti-aging protein SIRT1 gene expression is down-regulated. Experiments have been designed to examine sleep structure, the level of blood lipid, the circadian concentration of sex hormone and the expression of sex hormone receptor. For mechanistic study, we will examine the SIRT1 and circadian clock protein BMAL1 expressions in hypothalamus and liver tissues, as well as the changes of activity and expression of molecules involved in liver NAD+-mediated signaling pathway. Different experimental techniques including RT-PCR, Western-blot, HPLC will be used. The successful completion of the proposed research at integrative and molecular levels will illustrate the mechanisms of the dual actions of Jiao-tai-wan, based on which we will be able to develop a new anti-aging and biological rhythm-based treatment for postmenopausal NAFLD. Additionally, the proposed research will provide scientific foundations for the efficacy of Jiao-tai-wan and promote its wide use in clinical practice.