Genetic and Molecular Dissection of the Neurospora Clock

脉孢菌钟的遗传和分子解剖

• 批准号: 10330086
• 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/10330086
• 关键词: Address; Architecture; Biochemistry; Biological; Biological Clocks; Cell division; Cells; Circadian Rhythms; Complement; Development; Diabetes Mellitus; Disease; Dissection; Elements; Environment; Eukaryota; Feedback; Financial compensation; 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.

事实上，所有经过适当检查的真核生物都已被证明具有以下能力： 内源性时间控制和组织称为昼夜节律。细胞机器 负责产生节律的生物钟统称为生物钟。健康的生物钟 是身体和心理健康的基础。由于其对人类心理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。 我们的研究使用模型真核生物脉孢菌的遗传和分子研究，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，这是一种单 一步转录-翻译反馈环路，其调节结构从真菌到哺乳动物都是保守的。 计划的研究集中在三个重点领域。焦点＃1建立在我们对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如何 时钟组件之间导致反馈环路内的抑制；解决是否存在争议 负元素周转在哺乳动物振荡器中发挥作用；探究时钟如何控制磷酸化 指导时钟组件的基本相互作用和活动，从而产生规范的昼夜节律特性 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 开拓新领域并利用最近开发的技术， 扩大细胞生物学工具的使用来补充遗传学，以定义时空动态 细胞内的时钟组件。我们将展示时钟如何以及在单元中的何处运行。焦点#3 将建立在我们在光调节遗传学和基因组学方面的坚实基础上，利用计算和 信息工具来定义控制响应的转录因子的层次网络 脉孢菌对光和时间的影响。目的是为全球昼夜节律控制提供第一个具体模型 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循环 包括生物钟、该周期如何与环境同步以及时间信息如何 由反馈循环产生的反馈用于调节细胞和生物体的行为。这些项目是 互补和相互丰富，因为它们依靠遗传和分子技术来解剖，并且 最终了解细胞的组织是时间的函数。