Genetic and Molecular Dissection of the Neurospora Clock

脉孢菌钟的遗传和分子解剖

• 批准号: 10543515
• 负责人: Jay C. Dunlap
• 金额: $ 74万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543515
• 关键词: Address; Architecture; Biochemistry; Biological; Biological Clocks; Cell division; Cells; Circadian Rhythms; Compensation; Complement; Development; Diabetes Mellitus; Disease; Dissection; Elements; Environment; Eukaryota; Feedback; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Genome; Genomics; Goals; Human; Human body; Jet Lag Syndrome; Language; Lead; Light; Malignant Neoplasms; Mammalian Cell; Mammals; Mental Health; Mental Processes; Mental disorders; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Neurospora; New Territories; Nutritional; Organism; Phosphorylation; Physiological Processes; Physiology; Prevention; Property; RNA metabolism; Regulation; Repression; Research; Rest; Role; Sleep; Structure; Study models; Techniques; Temperature; Time; Translations; Work; cell behavior; circadian; circadian pacemaker; computerized tools; fungus; informatics tool; physical conditioning; response; shift work; spatiotemporal; tool; transcription factor; virtual

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.

几乎所有经过适当检查的真核生物都已证明具有能力 内源性时间控制和组织被称为昼夜节律。蜂窝机械 负责产生节奏的人被统称为生物钟。健康的昼夜节律 基础是身心健康。由于它对人类心理的影响无处不在 生理过程 - 从昼夜节律的基本人类生理学变化到明显的参与 工作/休息周期和睡眠的节奏 - 了解时钟是预防和治疗的基础 身体和精神疾病，从代谢疾病到睡眠/唤醒功能障碍和癌症。 我们的研究使用真核生神经模型的遗传和分子研究以及 培养中的哺乳动物细胞，以进一步了解昼夜节律振荡器的组织，一个 从真菌到哺乳动物的阶跃转录翻译反馈回路，其调节架构是保守的。 计划的研究在于三个焦点。焦点1建立在我们对之间的相互作用的理解之上 核心时钟组件中的结构和功能。我们将确定如何磷酸化和相互作用 在时钟组件中，导致反馈循环中的压制；解决是否存在争议 负元素更新在哺乳动物振荡器中起作用。探测时钟对照磷酸化的方式 指南的基本互动和时钟组件的活动，导致昼夜节日的典型属性 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先驱者新领土和利用最近开发了技术， 扩展使用细胞生物工具来补充遗传学，以定义时空动力学 电池内的时钟组件。我们将展示如何以及在单元格中的位置运行。焦点＃3 使用计算和 定义转录因素的层次结构网络的信息工具，该网络控制 神经孢子点亮和时间。目的是为全球昼夜节律的第一个具体模型提供 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 包括昼夜节律，该周期如何与环境同步以及时间信息 由反馈周期产生的用于调节细胞和生物的行为。这些项目是 互补和相互富裕的是，它们依赖于遗传和分子技术来剖析，并且 最终要理解，细胞的组织是时间的函数。