Pathophysilogy in evening-type : Observation in Clockmutant mice

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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.