Genetic and Molecular Dissection of the Neurospora Clock

 描述（由申请人提供）：几乎所有适当检查的真核生物都显示出具有内源性时间控制和组织的能力，称为昼夜节律。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。由于它对人类精神和生理过程的影响无处不在-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的明确参与-了解时钟是预防和治疗许多身心疾病的基础，从代谢紊乱到睡眠/觉醒功能障碍和癌症。我们的研究使用了真核生物模式脉孢菌的遗传和分子研究，以进一步了解昼夜节律振荡器的组织。计划的研究分为四个重点。焦点#1建立在我们对核心时钟组件中结构和功能之间相互作用的理解之上。新的数据与一些现有的模型和预测的时钟蛋白的作用不一致。我们将确定更新的角色，相互作用和结构，以及探索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集中在更深入地研究磷酸化在温度补偿中的作用以及引起这种作用的激酶。焦点#3建立在我们在遗传学和基因组学方面的坚实基础上，以及正在进行的工作，这些工作已经确定了三个新的基因，这些基因的突变改变了长达18小时的周期长度。对这些效应的基础的研究将把我们带入到迄今为止在昼夜节律生物学方面尚未探索的代谢和基因表达方面。焦点#4探索了全新的领域，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，探索一种新的遗传系统，尽管缺乏规范的时钟组件，但该系统仍会产生昼夜节律。我们的长期目标是用遗传学和生物化学的语言描述包括生物钟的反馈周期，这个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。这些项目是互补和相互丰富的，因为它们依赖于遗传和分子技术来解剖，并最终了解细胞组织作为时间的函数。

 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.