Effect of Temperature on Mammalian Circadian System

描述（由申请人提供）：昼夜节律，以24小时为尺度测量时间，是生物钟的明显结果。当与环境时间线索隔离时，昼夜节律振荡器以其自身的周期自由运行，该周期通常不同于24小时。然而，在光和温度的自然周期的存在下，昼夜节律振荡器被调整到正好24小时。由于这两种主要的环境信号在自然界中密切相关，因此温度循环的夹带效应模仿真菌，植物和变温动物中的光暗循环也就不足为奇了。然而，大多数科学家预测恒温动物不会受到温度的影响。然而，使用Per 1-luc转基因大鼠测量Per 1从培养的视交叉上核（SCN）的昼夜节律波动，我们已经表明，分离的SCN可以被幅度低至1 ℃的温度周期所夹带，在啮齿动物正常脑温度节律的范围内（1至1.5 ℃）。昼夜节律中的独特和基本现象之一是温度补偿;节律在很宽的温度范围内表现出相似的周期持续时间。虽然这种现象在近50年前就被发现了，但介导这种现象的生物化学或分子机制仍然不清楚。先前表明，哺乳动物SCN和视网膜中的节律是温度补偿的。我们的实验室最近证明，温度补偿也存在于外周细胞中。在这个提议中，温度对哺乳动物昼夜节律系统的两个主要影响：夹带和补偿将被分析。温度夹带是通过改变Per 1 mRNA水平介导的，而温度补偿是由三个周期基因的mRNA的不同降解速率的影响的假设将进行研究。 我们的建议的总体目标是确定分子的时钟机制的目标，负责证明温度的影响。本提案中获得的信息对于知情使用昼夜节律方法来理解和治疗人类的昼夜节律相关问题（如轮班工作，时差和时间癌症治疗）至关重要。

DESCRIPTION (provided by applicant): Circadian rhythms, which measure time on a scale of 24 h, are the overt consequences of biological clocks. When isolated from environmental time cues, a circadian oscillator free-runs with its own period which is usually different from 24 h. However, in the presence of the natural cycle of light and temperature, circadian oscillators are adjusted to exactly 24 h. Because these two major environmental signals are closely associated in nature, it is not surprising that the entraining effect of temperature cycles mimics that of the light-dark cycle in fungi, plants and poikilotherms. Most scientists, however, would predict that homeotherms would not be affected by temperature. Nevertheless, using Per1-luc transgenic rats to measure circadian fluctuations of Per1 from cultured suprachiasmatic nuclei (SCN), we have shown that the isolated SCN can be entrained by temperature cycles with an amplitude as low as 1 ¿C, well within the range of the normal brain temperature rhythm of rodents (1 to 1.5 ¿C). One of the unique and fundamental phenomena in circadian rhythms is temperature compensation; rhythms exhibit similar cycle durations over a wide range of temperatures. Although this phenomenon was discovered nearly 50 years ago, the biochemical or molecular mechanisms mediating this phenomenon are still not known. It was previously shown that the rhythms in the SCN and retina in mammals are temperature compensated. Our lab recently demonstrated that temperature compensation also exists in peripheral cells. In this proposal, the two major impacts of temperature on the mammalian circadian system: entrainment and compensation will be analyzed. The hypothesis that temperature entrainment is mediated by changing Per1 mRNA levels, whereas temperature compensation is affected by different degradation rates of mRNAs in three Period genes will be studied. The overall goal of our proposal is to identify molecular targets in the clock mechanism responsible for the demonstrated temperature effects. Information obtained in this proposal will be essential for the informed use of circadian approaches to the understanding and treatment of circadian-related concerns in humans, such as shift work, jet-lag, and chrono-cancer therapy.