Genetic and Molecular Dissection of the Neurospora Clock

脉孢菌钟的遗传和分子解剖

• 批准号: 9068385
• 负责人: Jay C. Dunlap
• 金额: $ 64.84万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068385
• 关键词: Architecture; Biochemistry; Biological; Biological Clocks; Biology; Cells; Circadian Rhythms; Clock protein; Complement; Data; Diabetes Mellitus; Disease; Dissection; Environment; Eukaryota; Feedback; Financial compensation; Functional disorder; Gene Expression; Genes; Genetic; Genomics; Goals; Hour; Human; Human body; Jet Lag Syndrome; Language; Length; Malignant Neoplasms; Mental Health; Mental Processes; Mental disorders; Metabolic Diseases; Metabolism; Modeling; Molecular Genetics; Mus; Mutation; Neurospora; New Territories; Organism; Phosphorylation; Phosphotransferases; Physiological Processes; Physiology; Prevention; Research; Rest; Role; Sleep; Structure; Study models; System; Techniques; Temperature; Time; Update; Work; base; cell behavior; circadian pacemaker; fungus; novel; physical conditioning; public health relevance; tool

 DESCRIPTION (provided by applicant): 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 has used genetic and molecular studies of the model eukaryote Neurospora to further our understanding of the organization of the circadian oscillator. Planned research lies within four foci. Focus #1 builds upon our understanding of the interplay between structure and function in core clock components. New data are inconsistent with some existing models and predicted roles for clock proteins. We will identify updated roles, interactions, and structures, as well as probing how clock-controlled phosphorylation guides essential interactions and activities of clock components. Focus #2 is centered on a deeper look at the role of phosphorylation in temperature compensation and the kinases that bring this about. Focus #3 builds upon our strong grounding in genetics and genomics as well as ongoing work that has identified three novel genes whose mutation alters period length by as much 18 hours. Examination of the bases of these effects will take us into aspects metabolism and gene expression heretofore unexplored in terms of circadian biology. Focus #4 explores completely new territory, pioneering the use of cell biological tools to complement genetics, exploring the regulatory plasticity of architecture of the circadian oscillator, and as time allows probing a novel genetic system that generates a circadian rhythm despite the absence of canonical clock components. 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.

 描述（由申请人提供）：几乎所有经过适当检查的真核生物都已被证明具有内源性时间控制和组织（称为昼夜节律）的能力。负责产生节律的细胞机制统称为生物钟。健康的生物钟是身心健康的基础。由于它对人类心理和生理过程的影响无处不在——从基本人类生理学的昼夜节律变化到工作/休息周期和睡眠中节律的明确参与——了解时钟是预防和治疗许多身体和精神疾病的基础，从代谢紊乱到睡眠/觉醒功能障碍和癌症。我们的研究利用真核生物脉孢菌模型的遗传和分子研究来进一步了解昼夜节律振荡器的组织。计划的研究集中在四个重点领域。焦点#1 建立在我们对核心时钟组件结构和功能之间相互作用的理解之上。新数据与一些现有模型和时钟蛋白的预测作用不一致。我们将确定更新的角色、相互作用和结构，并探讨时钟控制的磷酸化如何指导时钟组件的基本相互作用和活动。焦点#2 集中于更深入地研究磷酸化在温度补偿中的作用以及带来这种作用的激酶。焦点 #3 建立在我们在遗传学和基因组学方面的坚实基础以及正在进行的工作之上，该工作已确定了三个新基因，这些基因的突变会使经期长度改变多达 18 小时。对这些影响的基础的研究将带我们进入迄今为止在昼夜节律生物学方面尚未探索的新陈代谢和基因表达方面。焦点＃4探索全新的领域，开创性地使用细胞生物学工具来补充遗传学，探索昼夜节律振荡器结构的调节可塑性，并随着时间的推移探索一种新颖的遗传系统，该系统在缺乏规范时钟组件的情况下仍能产生昼夜节律。我们的长期目标是用遗传学和生物化学的语言描述包含生物钟的反馈周期，该周期如何与环境同步，以及反馈周期产生的时间信息如何用于调节细胞和生物体的行为。这些项目是互补且相互丰富的，因为它们依靠遗传和分子技术来剖析并最终理解细胞组织随时间的变化。