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。我们的内部生物钟调节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。与沙漏型定时器不同，生物钟型定时器（如昼夜节律钟）调节循环过程，这些过程在完成一个周期后会重复。几乎所有的细胞都是昼夜节律振荡器，了解这些时钟在细胞内的工作方式为整个动物水平的24小时节律提供了基础。细胞振荡器基于由转录激活因子和阻遏物组成的自动调节反馈环：阻遏物表达由激活因子上调，约12小时后由阻遏物本身下调。然而，确切地说，这些蛋白质是如何起作用来启动振荡和控制时钟的步伐的（即，时间长度）仍然难以捉摸。在该项目中，将使用分子和细胞遗传学方法，采用先进的实时生物发光技术，以阐明这些时钟蛋白的生化和功能特性，这些蛋白是建立和维持时钟功能的基础。来自细胞时钟模型的发现将在小鼠模型中进行验证和进一步探索，以获得生物学意义。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，而且对行为神经生物学的其他学科具有深远的一般意义，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。该项目采用多学科方法，研究昼夜节律组织（细胞，组织/器官和动物）多个水平的基因功能。因此，这项研究将为希望选择生物科学职业并在系统水平上研究基因功能的研究生和高年级本科生提供独特的综合培训机会。

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.