Biochemical and Molecular Basis of Circadian Behavior

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。我们体内的生物钟调节着行为和生理的许多重要方面，从睡眠-觉醒周期到体温和血压的日常变化。与沙漏型计时器不同，振荡型计时器（如生物钟）调节循环过程，在一个周期完成后将重复自己。几乎所有的细胞都是昼夜节律振荡器，了解这些时钟如何在细胞内工作，为整个动物水平的24小时节律提供了基础。细胞振荡子基于一个由转录激活因子和阻遏因子组成的自调节反馈回路：阻遏因子的表达由激活因子上调，约12小时后由阻遏因子自身下调。然而，这些蛋白质究竟是如何启动振荡和控制生物钟的节奏（即周期长度）的，仍然是难以捉摸的。在这个项目中，分子和细胞遗传学方法将使用先进的实时生物发光技术，来阐明这些时钟蛋白的生化和功能特性，这些特性是时钟功能建立和维持的基础。细胞时钟模型的发现将在小鼠模型中得到验证并进一步探索其生物学意义。该项目不仅有望显著提高我们对昼夜节律行为的生化基础的理解，而且还将对行为神经生物学的其他学科产生深远的一般影响，有助于破译细胞和分子事件如何将基因与复杂行为联系起来。本项目采用多学科方法，在昼夜节律组织（细胞、组织/器官和动物）的多个水平上研究基因功能。因此，这项研究将为希望在生物科学领域选择职业并在系统水平上研究基因功能的研究生和高级本科生提供独特的综合训练机会。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).Our internal biological clocks regulate many important aspects of behavior and physiology, from sleep-wake cycle to daily changes in body temperature and blood pressure. Unlike hourglass-type of timers, the oscillator-type of timers such as the circadian clock regulates cyclic processes that will repeat itself upon completion of a cycle. Virtually all cells are circadian oscillators, and understanding how these clocks work inside cells provides the basis for the 24-hr rhythms at the whole animal level. The cellular oscillators are based on an auto-regulatory feedback loop consisting of transcriptional activators and repressors: repressor expression is up regulated by the activators, and ~12 hr later down regulated by the repressors themselves. However, exactly how these proteins function to initiate oscillation and to control the pace of the clock (i.e., period length) remains elusive. In this project molecular and cellular genetic approaches will be used, powered with advanced real-time bioluminescence technology, to elucidate the biochemical and functional properties of these clock proteins that underlie the establishment and maintenance of clock function. Findings from cellular clock models will be validated and further explored in mouse models for biological significance. This project is expected to not only significantly improve our understanding of the biochemical basis of circadian behavior, but also have profound general implications for other disciplines in behavioral neurobiology, helping to decipher how cellular and molecular events connect genes to complex behavior. This project employs multidisciplinary approaches and investigates gene function at multiple levels of circadian organization (cells, tissues/organs, and animals). This research will thus provide unique and integrative training opportunities for graduate and advanced undergraduate students who wish to choose a career in biological sciences and to study gene function at the systems level.