Genetic and Molecular Dissection of the Neurospora Clock

事实上，所有经过适当检查的真核生物都显示出具有以下能力： 内源性时间控制和组织称为昼夜节律。的细胞机器 负责产生节奏的生物钟统称为生物钟。健康的生物钟 是身心健康的基础由于它对人类精神和心理的影响无处不在， 生理过程-从基本人体生理学的昼夜节律变化到 工作/休息周期和睡眠的节奏-了解生物钟是预防和治疗许多疾病的基础。 身体和精神疾病，从代谢紊乱到睡眠/觉醒功能障碍和癌症。 我们的研究使用了真核生物模式脉孢菌的遗传和分子研究，以及 培养的哺乳动物细胞，以进一步了解昼夜节律振荡器的组织，一个- 逐步转录-翻译反馈环，其调控结构从真菌到哺乳动物都是保守的。 计划的研究分为三个重点。焦点#1建立在我们对以下因素之间相互作用的理解之上： 核心时钟组件的结构和功能。我们将确定磷酸化和相互作用 在时钟组件之间导致反馈回路内的抑制;解决关于是否 负元件周转在哺乳动物振荡器中有作用;探测时钟如何控制磷酸化 指导生物钟组成部分的基本相互作用和活动，导致生物钟的典型昼夜节律特性。 温度补偿，以及RNA代谢和基因表达的调节如何有助于 营养补偿焦点#2开拓新的领域，利用最近开发的技术， 扩大细胞生物学工具的使用，以补充遗传学，确定时空动态的 细胞内的时钟。我们将展示时钟是如何工作的，以及在细胞中的什么地方工作。焦点#3 将建立在我们在光调节的遗传学和基因组学的坚实基础上，使用计算和 信息学工具来定义控制免疫应答的转录因子的分层网络， 脉孢菌对光线和时间的反应。其目的是提供第一个具体的全球昼夜节律控制模型， 真核基因组 我们的长期目标是用遗传学和生物化学的语言来描述反馈循环 包括生物钟，这个周期如何与环境同步，以及时间信息如何与环境同步。 由反馈循环产生的能量被用来调节细胞和生物体的行为。这些项目 互补和相互丰富，因为它们依赖于遗传和分子技术来解剖， 最终理解细胞的组织是时间的函数。

Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization known as a circadian rhythm. The cellular machinery responsible for generating rhythms is collectively known as the biological clock. A healthy circadian clock underlies both physical and mental health. Because of the ubiquity of its influence on human mental and physiological processes - from circadian changes in basic human physiology to the clear involvement of rhythms in work/rest cycles and sleep - understanding the clock is basic to prevention and treatment of many physical and mental illnesses, from metabolic disorders to sleep/wake dysfunction and cancer. Our research uses genetic and molecular studies of the model eukaryote Neurospora, as well as mammalian cells in culture, to further our understanding of the organization of the circadian oscillator, a one- step transcription-translation feedback loop whose regulatory architecture is conserved from fungi to mammals. Planned research lies within three foci. Focus #1 builds upon our understanding of the interplay between structure and function in core clock components. We will determine how phosphorylations and interactions among clock components lead to repression within the feedback loop; address a controversy as to whether negative element turnover has a role in the mammalian oscillator; probe how clock-controlled phosphorylation guides essential interactions and activities of clock components leading to the canonical circadian property of temperature compensation, and how modulation of RNA metabolism and gene expression contribute to nutritional compensation. Focus #2 pioneers new territory and exploits recently developed techniques, expanding the use of cell biological tools to complement genetics in defining the spatio-temporal dynamics of clock components within the cell. We will show how, as well as where in the cell the clock operates. Focus #3 will build upon our strong grounding in the genetics and genomics of light-regulation, using computational and informatic tools to define the hierarchical network of transcription factors that govern the response of Neurospora to light and time. The aim is to provide the first concrete model for global circadian control of a eukaryotic genome. Our long term goals are to describe, in the language of genetics and biochemistry, the feedback cycle comprising the circadian clock, how this cycle is synchronized with the environment, and how time information generated by the feedback cycle is used to regulate the behavior of cells and organisms. These projects are complementary and mutually enriching in that they rely on genetic and molecular techniques to dissect, and ultimately to understand, the organization of cells as a function of time.