Pathophysilogy in evening-type : Observation in Clockmutant mice

生物钟相关基因的发现为昼夜节律系统的分子机制提供了证据。CLOCK和BMAL 1相互联合收割机并作为阳性成分。正元件与Par 1或Per 2主要振荡基因DNA上的E-box结合，增强其转录。增加的PER 1和PER 2联合收割机与ER 1、ER 2和其他一些蛋白结合，作为负成分负成分移回细胞核，抑制正成分的功能。这种负反馈回路被认为是造成昼夜节律振荡的原因。我们认为Clock突变小鼠表现出夜间型的睡眠、运动和体温昼夜节律。通过本课题的研究，我们获得了以下新的发现：1）Clock突变小鼠的心血管控制Clock突变小鼠血压和心率呈现“非浸渍型”昼夜节律。研究表明，这种变化可能与肾上腺功能有关。2）Clock突变小鼠的学习能力Clock突变小鼠的空间学习能力受损。PPARs的一种配体对睡眠、行为和体温的作用长期服用PPARs激动剂苯扎贝特，可使睡眠、行为和体温的昼夜节律提前，并在NREM睡眠期间增加δ功率，抑制6- 10天后的稳态增加。我们已经证明Clock基因具有多种生理功能，特别是在心血管或代谢功能方面。Clock基因被认为是代谢综合征预防的重要靶点之一。

From the discovery of clock-related genes, evidences on the molecular mechanism of circadian system have been accumulated. CLOCK and BMAL1 combine each other and act as Positive Component. The positive element combines with E-box on DNA for Par1 or Per2 main oscillating genes, and enhances its transcription. Increased PER1 and PER2 combine with CRY1, CRY2 and some other proteins and act as Negative Component Negative Component moves back to nucleus and suppress the function of Positive Component. This negative feedback loop is considered to make circadian oscillation. We bind that Clock mutant mice show the evening-type circadian rhythm of sleep, locomotion and body temperature. By this project, we have got the new findings as follows;1) Cardiovascular control in Clock mutant miceClock mutant mice show "non-dipping type" diurnal rhythm of blood pressure and heart rate. It has been suggested that adrenal function may be involved in this change.2) Learning ability in Clock mutant miceClock mutant mice show impaired spatial learning ability. It has been suggested that this impairment may be related with the decreased acetylcholine release in hippocampus.3) Role of a ligand of PPARs on sleep, behavior and body temperatureChronic administration of bezafibrate, a PPARs agonist, causes the advance of the diurnal rhythm of sleep, behavior and body temperature, and augments the delta power during NREM sleep suppressing the homeostatic increase after 6-hr sleep deprivation.We have demonstrated that Clock gene has a variety of physiological function especially on the cardiovascular or metabolic function. For prevention of metabolic syndrome, Clock gene is considered to be one of the important targets.