Identification and Analysis of Circadian Clock-Controlled Genes

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。由于它对人类心理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-了解生物钟是预防和治疗许多身心疾病的基础。 我们的具体目标旨在进一步了解生物钟调节细胞行为的方式，包括细胞生长和某些癌症。具体目标#1建立在我们鉴定细胞周期调节剂检查点激酶2作为脉孢菌中时钟功能的条件修饰剂的基础上。我们将在培养的哺乳动物细胞和小鼠中进行这项工作，以探索昼夜节律系统和细胞周期的相互联系。具体目标#2建立在我们对脉孢菌中非昼夜输出振荡器的持续分析基础上，作为介导昼夜输出的重要手段。我们将识别输出振荡器的组件，并确定它们与昼夜节律周期连接的方式。具体目标#3建立在我们在基因组学方面的坚实基础之上。我们将对输出振荡器的组成部分进行过表达筛选和敲除筛选，并将使用微阵列来识别脉孢菌中的时钟控制和输出振荡器控制的基因。 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，并最终了解细胞的组织作为时间的函数。公共卫生相关性：事实上，所有经过适当研究的真核生物都被证明具有内源性时间控制和组织的能力，称为昼夜节律，生物钟的输出。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-了解生物钟是预防和治疗许多身心疾病的基础。

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. Our specific aims are designed to further our understanding of the means through which the clock regulates cell behavior, including cell growth and in some cases cancer. Specific Aim #1 builds upon our identification of the cell cycle regulator checkpoint kinase 2 as a conditional modifier of clock function in Neurospora. We will pursue this work in mammalian cells in culture and in mice to probe the interconnectedness of the circadian system and cell cycle. Specific Aim #2 builds upon our ongoing analysis of non-circadian output oscillators in Neurospora as an important means of mediating circadian output. We will identify components of output oscillators and determine the means through which they are connected to the circadian cycle. Specific Aim #3 builds upon our strong grounding in genomics. We will carry out an overexpression screen and a knockout screen for components of output oscillators and will use microarrays to identify the clock-controlled and output oscillator-controlled genes in Neurospora. 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 the cell as a function of time. PUBLIC HEALTH RELEVANCE: 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 output of a 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.