Effect of Temperature on Mammalian Circadian System

描述(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的周期通常与24小时不同。然而，在自然光和温度周期的存在下，昼夜节律振荡器被调整到恰好24小时。由于这两个主要环境信号在自然界中密切相关，难怪温度周期的携带效应与真菌、植物和变温动物的光暗周期相似。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PER1-Luc转基因大鼠来测量培养的视交叉上核(SCN)中PER1的昼夜波动，我们发现分离的SCN可以被低至1℃的温度循环所携带，完全在啮齿类动物正常脑温节律(1~1.5℃)的范围内。昼夜节律中独特而基本的现象之一是温度补偿；在广泛的温度范围内，节律表现出类似的周期持续时间。虽然这一现象在近50年前就已被发现，但调节这一现象的生化或分子机制仍不清楚。以前的研究表明，哺乳动物的SCN和视网膜的节律是温度补偿的。我们的实验室最近证实，外周细胞也存在温度补偿。在这项提案中，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。我们将研究这样一种假设，即温度夹带是通过改变PER1mRNA水平来调节的，而温度补偿是由三个周期基因中不同的mRNAs降解速度所影响的。 我们建议的总体目标是在时钟机制中确定负责所展示的温度效应的分子靶标。在这项建议中获得的信息对于知情地使用昼夜节律方法来理解和治疗人类与昼夜节律相关的问题至关重要，例如轮班工作、时差和时序癌症治疗。

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.