Genetic and Molecular Dissection of the Neurospora Clock

几乎所有经过适当检查的真核生物都被证明具有 内源性的时间控制和组织称为昼夜节律。蜂窝机械 负责产生节律的生物钟统称为生物钟。健康的生物钟 身体健康和心理健康都是基础。因为它对人类精神和心理的影响无处不在 生理过程--从人体基本生理学的昼夜节律变化到 工作/休息周期和睡眠的节奏-了解时钟是预防和治疗许多 身体和精神疾病，从新陈代谢障碍到睡眠/唤醒功能障碍和癌症。 我们的研究使用了模式真核生物脉孢子虫的遗传和分子研究，以及 哺乳动物细胞的培养，为了加深我们对昼夜节律振荡器组织的理解，一个- 步进转录-翻译反馈环，其调控结构从真菌到哺乳动物都是保守的。 计划中的研究集中在三个方面。焦点#1建立在我们对相互作用的理解之上 核心时钟组件中的结构和功能。我们将确定磷酸化和相互作用如何 在时钟组件之间导致反馈环路内的抑制；解决关于是否 负元素周转在哺乳动物振荡器中起作用；探索时钟如何控制磷酸化 引导时钟分量的基本相互作用和活动导致正则昼夜节律特性 温度补偿，以及RNA新陈代谢和基因表达的调节如何有助于 营养补偿。Focus#2开创了新的领域，并利用了最近开发的技术， 扩大细胞生物学工具的使用，以补充遗传学定义的时空动力学 单元内的时钟组件。我们将展示时钟是如何运行的，以及在细胞中的哪个位置运行。焦点#3 将建立在我们在光调节的遗传学和基因组学方面的坚实基础上，使用计算和 用于定义转录因子层级网络的信息学工具，这些转录因子控制 脉孢子虫对光和时间的影响。其目的是为全球昼夜节律控制提供第一个具体的模型 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描述反馈周期 包括生物钟，这个周期如何与环境同步，以及时间信息 所产生的反馈循环被用来调节细胞和生物体的行为。这些项目是 它们依靠基因和分子技术进行解剖，这是相辅相成和相互丰富的 最终要理解的是，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.