德州大学西南医学中心的Zheng Chen等近日在美国国家科学院院刊（Proceedings of the National Academy of Sciences）发表论文称，发现了调节生物钟节律的关键分子。改发现对生物钟研究具有重大意义。
生物钟在调节人体正常的生理活动中起重要作用，主要负责调节体内各系统的周期性变化，其出现异常往往与慢性疾病和衰老等有关。
Zheng Chen等通过一种可持续性监视小鼠模型生理周期的高通量分析方法，研究了约200000种人造小分子化合物对生理节奏的影响。
研究人员发现了4种分子可同时延长中心和外周节律周期，这些节律器是哺乳动物各个层次的生物钟系统的重要组成部分，对生物的周期性生理活动起重要调节作用。另外2种化合物可延迟并抑制生物钟节律，且不受细胞内关键信号分子cAMP水平升高的影响。
更重要的是，另外5种化合物可以缩短外周生物钟周期，其中4种可增大中心和外周生物钟节律的波动幅度。
作者称，这些发现对生物钟节律调节机制的研究有重要意义，并有助于研发用于治疗生物钟紊乱相关性疾病的治疗药物。（生物谷bioon.com）
doi:10.1073/pnas.1118034108
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Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening
Zheng Chen, Seung-Hee Yoo, Yong-Sung Park, Keon-Hee Kim,Shuguang Wei, Ethan Buhr, Zeng-You Ye, Hui-Lin Pan, andJoseph S. Takahashi.
The circadian clock coordinates daily oscillations of essential physiological and behavioral processes. Conversely, aberrant clocks with damped amplitude and/or abnormal period have been associated with chronic diseases and aging. To search for small molecules that perturb or enhance circadian rhythms, we conducted a high-throughput screen of approximately 200,000 synthetic compounds usingPer2∷lucSV reporter fibroblast cells and validated 11 independent classes of molecules with Bmal1:luciferase reporter cells as well as with suprachiasmatic nucleus and peripheral tissue explants. Four compounds were found to lengthen the period in both central and peripheral clocks, including three compounds that inhibited casein kinase Iε in vitro and a unique benzodiazepine derivative acting through a non-GABAA receptor target. In addition, two compounds acutely induced Per2∷lucSV reporter bioluminescence, delayed the rhythm, and increased intracellular cAMP levels, but caused rhythm damping. Importantly, five compounds shortened the period of peripheral clocks; among them, four compounds also enhanced the amplitude of central and/or peripheral reporter rhythms. Taken together, these studies highlight diverse activities of drug-like small molecules in manipulating the central and peripheral clocks. These small molecules constitute a toolbox for probing clock regulatory mechanisms and may provide putative lead compounds for treatment of clock-associated diseases.
