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。当与环境时间线索分离时，昼夜节律振荡器自由运行，其周期通常与24小时不同。然而，在存在自然光和温度循环的情况下，昼夜节律振荡器被调整到恰好24小时。因为这两个主要的环境信号在自然界中密切相关，因此温度周期的携带效应模仿真菌、植物和变温动物的光暗循环并不奇怪。然而，大多数科学家会预测恒温动物不会受到温度的影响。然而，使用Per1-luc转基因大鼠测量培养的视交叉上核（SCN）中Per1的昼夜波动，我们已经表明，分离的SCN可以被振幅低至1°C的温度周期所携带，完全在啮齿动物正常大脑温度节律（1至1.5°C）的范围内。昼夜节律中一个独特而基本的现象是温度补偿；在很宽的温度范围内，节律表现出相似的周期持续时间。虽然这一现象在近50年前就被发现了，但介导这一现象的生化或分子机制尚不清楚。以前的研究表明，哺乳动物的视细胞核和视网膜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。本文将分析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。假设温度携带是通过改变Per1 mRNA水平介导的，而温度补偿是由三个周期基因中mRNA的不同降解速率影响的。

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.