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STUDY ON MECHANISM AND TREATMENT OF JET LAG CAUSED BY DISSOCIATION OF TWO OSILLATORS.

两个振荡器分离所致时差反应的机理及治疗研究。

基本信息

批准号：
13557007
负责人：
SHIGEYOSHI Yasufumi
金额：
$ 1.09万
依托单位：
KINKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557007/
关键词：
INTERNAL CLOCK CIRCADIAN RHYTHM CLOCK GENES Rev-erb JET LAG Per1 cAMP SUPRACHIASMATIC NUCLEUS 慨日周期位相変位

项目摘要

A. Dichotomy of the circadian center is associated with jet lag syndromeIn both 10 hour delay and 6 hour advance of light-dark cycle, we found that there appeared the dissociation of the suprachiasmatic into two oscillators. The ventrolateral region of the SCN (VLSCN) shifted rapidly whereas the dorsomedial regions of the SCN (DMSCN) shifted very slowly, spent more than a week to regain synchronization of the VLSCN and VLSCN. The sluggish shift of the DMSCN corresponds to the suppressed locomotors activity, which suggests that jet lag is caused by the slow shift of the DMSCN after LD cycle shift.B. Transgene of mammalian Per2 genes to Per2-null Drosophila mutants recovered the circadian rhythmicity.We introduced transgene to Per2-null Drosophila of which activity is arrhythmic. In the Drosophila expressing mouse Per21 or Per22 gene, we found the recovery of locomotor rhythms. The finding suggests that Pa-21 and Per22 have similar roles of clock genes even in the mammalian species.C. A Transcription Factor Response Element for Gene Eypressinn During Circadian NightWe profiled suprachiasmatic nuclei (SCN) and liver genome-wide expression patterns under light/dark (LD) cycles and constant darkness (DD). We extensively determined transcription start sites (TSS) of human orthologues for newly identified cycling genes and then Per2 formed bioinformatical searches for relationships between time-of-day specific expression and transcription factor response elements around TSS. We demonstrate the role of the Rev-ErbA/ROR response element in gene expression of nocturnally expressed genes in SCN and liver.D. Phosphodiesterase type,4 (PDE4) specifically degradg cAMPTo enhance Per21 transcription by the inhibition of cAMP degradation, we used Rolipram, a specific inhibitor of phosphodiesterase type 4 which degrades the cAMP. We found that the Per21 transcript increased transiently but the Per2iod length of Per21 increase was not extended.

在光暗周期延迟10小时和提前6小时时，我们发现视交叉上区出现了分裂为两个振荡区。SCN的腹外侧区（VLSCN）移动迅速，而SCN的背内侧区（DMSCN）移动非常缓慢，需要一周多的时间才能恢复VLSCN和VLSCN的同步。DMSCN的缓慢移位与运动活动的抑制相对应，提示时差反应是由LD周期移位后DMSCN的缓慢移位引起的。将哺乳动物的Per2基因转化为Per2缺失的果蝇突变体，恢复了果蝇的昼夜节律性。我们将转基因引入了活性不规律的Per2-null果蝇。在表达小鼠Per21或Per22基因的果蝇中，我们发现运动节律恢复。这一发现表明，即使在哺乳动物物种中，Pa-21和Per22也具有相似的时钟基因作用。研究人员分析了视交叉上核（SCN）和肝脏在光照/黑暗（LD）周期和持续黑暗（DD）条件下的全基因组表达模式。我们广泛地确定了新发现的循环基因的人类同源物的转录起始位点（TSS），然后Per2形成了生物信息学搜索，以寻找TSS周围的时间特异性表达和转录因子应答元件之间的关系。我们证明了Rev-ErbA/ROR反应元件在SCN和肝脏夜间表达基因的基因表达中的作用。磷酸二酯酶4 （PDE4）特异性降解cAMP，为了通过抑制cAMP降解来增强Per21的转录，我们使用了Rolipram，一种降解cAMP的磷酸二酯酶4的特异性抑制剂。我们发现Per21转录本短暂增加，但Per21增加的周期长度没有延长。