基于生物钟基因Cry探讨姜黄素干预慢性应激大鼠胰岛素抵抗的分子机制

在前期研究发现姜黄素具有抗抑郁和改善胰岛素抵抗作用的基础上，本课题从调节生物钟基因的角度探讨姜黄素干预抑郁症并发胰岛素抵抗的分子机制。隐花色素（Cry）是一种生物钟关键调控基因，通过负反馈机制调节生物体昼夜节律变化。Cry的异常表达可导致生理节律的紊乱。最近研究发现，Cry与抑郁症和糖尿病密切相关。本课题以慢性应激模拟人类抑郁症的环境诱因，建立抑郁合并胰岛素抵抗大鼠模型；以肝脏Cry为切入点，探讨生物钟基因异常表达在抑郁症并发胰岛素抵抗病理机制中的关键作用；以姜黄素为研究对象，系统评价姜黄素对慢性应激大鼠肝脏Cry的调节作用，并探讨其上游调控机制，阐明姜黄素通过调节生物钟基因以改善慢性应激大鼠胰岛素抵抗的分子机制。本课题将从调节生物钟基因的角度为开发抑郁并发胰岛素抵抗的治疗药物提供新思路。

On the basis of our previous study that curcumin could improve the depression and insulin resistance, this proposal is designed to explore the molecular mechanisms of curcumin in the treatment of depression combined with insulin resistance based on the regulation of circadian clock genes. Cryptochrome (Cry) is a key regulatory gene of circadian clock, and it regulates circadian rhythm through negative feedback mechanisms. Abnormal expression of Cry can lead to circadian rhythm disorders. Recently, Cry was found to have a close relationship with depression and T2D. This work is planned to build a rat model of depression combined with insulin resistance using chronic stress as stimulating factors. Firstly, we investigate the key roles of abnormal expression of Cry in liver in the pathogenesis of depression combined with insulin resistance. Secondly, to elucidate the molecular mechanisms improving insulin resistance in chronic stress rats, we evaluate the effects of curcumin on Cry expression in liver, and explore the upstream regulation mechanisms. This research will provide a new direction for the development of therapeutic drugs in treatment of depression combined with insulin resistance.