Molecular dissection of the mammalian circadian clock: The roles of the deubiquitinase USP2 in the circadian system

生理学的许多方面都存在24小时（或昼夜）节律：睡眠-觉醒周期，进食，激素，体温等。这些昼夜节律允许生物体适当地适应环境的周期变化（昼夜周期，季节）。昼夜节律是由“生物钟”产生的，生物钟位于大脑和其他各种器官中。近年来，许多所谓的“时钟基因”被发现，这些基因构成了生物钟的齿轮。我的研究计划的总体目标是准确地了解这些生物钟的功能以及它们如何控制生理和行为。最近，我们发现了生物钟的一个新组成部分，一种名为USP 2的蛋白质。这种蛋白质似乎改变了其他时钟组件的工作方式。因此，该提案描述了未来五年的工作，旨在找到USP 2在生物钟中的确切作用。更具体地说，我们希望了解USP 2如何与生物钟的其他齿轮协同工作，它如何帮助生物钟对环境昼夜周期做出反应，以及它如何允许细胞中的各种过程在一天中发生变化。总的来说，这里描述的工作将揭示直接将分子时钟与生理和细胞功能联系起来的重要机制。此外，这项研究计划将允许许多学生在分子生物学，神经科学和时间生物学方面的不同专业知识的培训。

Numerous aspects of physiology present 24-hour (or circadian) rhythms: sleep-wake cycles, feeding, hormones, body temperature, etc. These circadian rhythms allow the organism to adapt properly to cyclic variations of the environment (day-night cycles, seasons). Circadian rhythms are generated by "biological clocks", which are located in the brain as well as in various other organs. In recent years, many so-called "clock genes" have been discovered; these genes constitute the cogwheels of the biological clocks. The general objective of my research program is to understand exactly how these circadian clocks function and how they control physiology and behaviour. Recently, we found a new component of the biological clock, a protein called USP2. This protein seems to modify how other clock components work. Thus, this proposal describes the work of the next five years aiming at finding the exact role of USP2 within the biological clocks. More specifically, we wish to find out how USP2 works in concert with other gears of the biological clock, how it helps the clock to respond to environmental day-night cycles and how it allows various processes in cells to vary over the day. Overall the work described here will shed new light on important mechanisms that directly link molecular clocks with physiology and cell functions. Moreover, this research program will allow the training of many students with a diverse expertise in molecular biology, neuroscience and chronobiology.