德州大學(xué)西南醫(yī)學(xué)中心的Zheng Chen等近日在美國(guó)國(guó)家科學(xué)院院刊（Proceedings of the National Academy of Sciences）發(fā)表論文稱,，發(fā)現(xiàn)了調(diào)節(jié)生物鐘節(jié)律的關(guān)鍵分子,。改發(fā)現(xiàn)對(duì)生物鐘研究具有重大意義,。
生物鐘在調(diào)節(jié)人體正常的生理活動(dòng)中起重要作用，主要負(fù)責(zé)調(diào)節(jié)體內(nèi)各系統(tǒng)的周期性變化,，其出現(xiàn)異常往往與慢性疾病和衰老等有關(guān),。
Zheng Chen等通過(guò)一種可持續(xù)性監(jiān)視小鼠模型生理周期的高通量分析方法，研究了約200000種人造小分子化合物對(duì)生理節(jié)奏的影響,。
研究人員發(fā)現(xiàn)了4種分子可同時(shí)延長(zhǎng)中心和外周節(jié)律周期,，這些節(jié)律器是哺乳動(dòng)物各個(gè)層次的生物鐘系統(tǒng)的重要組成部分,，對(duì)生物的周期性生理活動(dòng)起重要調(diào)節(jié)作用。另外2種化合物可延遲并抑制生物鐘節(jié)律,，且不受細(xì)胞內(nèi)關(guān)鍵信號(hào)分子cAMP水平升高的影響。
更重要的是,，另外5種化合物可以縮短外周生物鐘周期,，其中4種可增大中心和外周生物鐘節(jié)律的波動(dòng)幅度。
作者稱,，這些發(fā)現(xiàn)對(duì)生物鐘節(jié)律調(diào)節(jié)機(jī)制的研究有重要意義,，并有助于研發(fā)用于治療生物鐘紊亂相關(guān)性疾病的治療藥物。（生物谷bioon.com）
doi:10.1073/pnas.1118034108
PMC:
PMID:
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.
