MOLECULAR MECHANISMS OF THE NEUROSPORA CIRCADIAN CLOCK

神经孢子虫昼夜节律的分子机制

• 批准号: 6628951
• 负责人: YI LIU
• 金额: $ 24.96万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628951
• 关键词: Neurospora; circadian rhythms; enzyme activity; fungal genetics; fungal proteins; gene induction /repression; laboratory rabbit; microorganism metabolism; phosphoproteins; point mutation; polysomes; proteasome; protein kinase; serine; temperature; ubiquitin; yeast two hybrid system

DESCRIPTION (From the Applicant's Abstract): The long term goal of this project is to understand the molecular mechanism of circadian clocks in eukaryotic cells. Circadian clocks are fundamental cellular processes by which almost all organisms use to keep time, and they control a wide variety of cellular, physiological, and behavioral activities. The importance of circadian clock in human physiology and mental health is evident from its ubiquitous influence on a wide range of cellular and physiological processes, including sleep/wake and body temperature cycles, endocrine functions, drug tolerance and resistance, and jet lag. The malfunction of the clock is known to be associated with several forms of human psychiatric illness and sleep disorders. Despite their importance, however, clues to the underlying molecular mechanism are only just beginning to emerge. To achieve our goal, we are focusing our studies in the model system Neurospora crassa, which has one of the best understood clock systems. In Neurospora, frequency (frq) gene is an essential regulatory component in the clock. We have found that frq gene product, FRO, is progressively phosphorylated and the phosphorylation of FRO is important for its degradation and the clock function. In Specific Aim 1, we will use both genetic and biochemical approaches to identify the kinase(s) that phosphorylates FRO. The gene(s) encoding the kinase(s) will be cloned and its clock function analyzed. We know that the degradation of FRO is an important regulatory aspect of the clock, therefore, the understanding the mechanism by which FRO is degraded will be our focus in Specific Aim 2. We will test several specific hypotheses of the mechanism of FRO degradation, and we will examine the role of FRO degradation in the clock. Temperature is a major clock affecting environmental factor and it affects several fundamental clock properties for all circadian clocks. In Specific Aim 3, we will study the molecular mechanisms of temperature regulations in the Neurospora clock. Specifically, we will study how temperature regulates the expression of FRO and the molecular mechanism of temperature compensation of the clock. Together, these studies will allow us to describe the framework of the Neurospora clock in genetic and molecular terms.

描述（来自申请人的摘要）：该项目的长期目标 是为了了解真核生物钟的分子机制 细胞。昼夜节律钟是基本的细胞过程，几乎所有生物钟都通过它 生物体用来计时，它们控制着多种细胞， 生理和行为活动。生物钟的重要性 人类生理和心理健康的普遍影响显而易见 广泛的细胞和生理过程，包括睡眠/觉醒和 体温循环、内分泌功能、药物耐受性和耐药性、 和时差。众所周知，时钟故障与 几种形式的人类精神疾病和睡眠障碍。尽管他们的 然而，潜在分子机制的线索仅是重要的 开始出现。为了实现我们的目标，我们的研究重点是 粗糙脉孢菌模型系统，它具有最容易理解的时钟之一 系统。在脉孢菌中，频率（frq）基因是一个重要的调节基因 时钟中的组件。我们发现 frq 基因产物 FRO 是 FRO 逐渐磷酸化，并且 FRO 的磷酸化对于 它的退化和时钟功能。在具体目标 1 中，我们将同时使用 遗传和生化方法来鉴定激酶 磷酸化FRO。编码激酶的基因将被克隆，并且其 分析时钟功能。我们知道FRO的降解是一个重要的因素 时钟的调节方面，因此，通过以下方式理解该机制 哪个FRO被降级将是我们在Specific Aim 2中的重点。我们将测试几个 FRO降解机制的具体假设，我们将研究 FRO 退化在时钟中的作用。温度是一个主要时钟 影响环境因素，影响几个基本时钟 所有生物钟的属性。在具体目标 3 中，我们将研究 脉孢菌钟温度调节的分子机制。 具体来说，我们将研究温度如何调节 FRO 和 时钟温度补偿的分子机制。一起， 这些研究将使我们能够描述脉孢菌时钟的框架 在遗传和分子方面。