The FRH DEXH box helicase: analysis of a core component of the Neurospora circadi

FRH DEXH 盒式解旋酶：圆脉脉孢菌核心成分的分析

• 批准号: 8059480
• 负责人: Jennifer Hurley
• 金额: $ 4.84万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059480
• 关键词: Affect; Alleles; Animals; Architecture; Awareness; Behavioral; Binding; Biochemical; Boxing; Cardiovascular Diseases; Cells; Circadian Rhythms; Co-Immunoprecipitations; Complex; Cues; Cyanobacterium; Ecology; Effectiveness; Elements; Escherichia coli; Family; Frequencies; Gene Frequency; Genes; Health; Homologous Gene; Hour; Human; Knock-out; Life; Link; Malignant Neoplasms; Mass Spectrum Analysis; Medical; Mental disorders; Messenger RNA; Neurospora; Periodicity; Physiological; Play; Process; Protein Family; Proteins; RNA; RNA Helicase; Role; SKIV2L gene; Sequence Homology; Signal Transduction; Sleep Disorders; System; Time; Work; cell growth; cellular development; circadian pacemaker; helicase; human disease; insight; mutant; novel; protein expression; response; white collar 1

DESCRIPTION (provided by applicant): Circadian rhythms are a roughly 24-hour cycle in the biochemical, physiological or behavioral processes of living entities and are present from animals to cyanobacteria. A circadian rhythm is defined as a cycle that has a period of about a single day, can persist in the absence of time cues while retaining the ability to be reset by them, and is not affected by signals outside these cues. The proteins that constitute the core components of the Neurospora clock, one of the best-studied circadian systems, include Frequency (FRQ), White Collar 1 (WC-1), White Collar 2 (WC-2) and Frequency Interacting RNA Helicase (FRH). While the first three components are well studied, many questions remain about the role that FRH plays in the function of the Neurospora clock. The aim of this work is to identify the function of FRH in the Neurospora circadian clock. To investigate this mechanism, I will use a multi-facetted approach. In Specific Aim 1, I will identify the regions of FRH that are essential to cellular growth and development, and distinguish them from regions that are related to the function of the circadian clock using the FRHR806H strain; a strain in which the rhythmicity of the clock is knocked out while maintaining the health of the strain. In Specific Aim 2, to further understand the function and importance of FRH, I will look at the interactions between the other core components and FRH, while identifying the regions of FRH important for each interaction. In Specific Aim 3, I will determine the RNA targets of FRH and explore its role as an mRNA interacting protein, a function that is suggested by its homology to the DEAD box family of proteins, in particular the DSHCT family. Because of its similarity to DEAD-box proteins it is logical to assert that FRH may facilitate the interaction of clock controlled gene mRNAs with necessary partners. This would demonstrate an entirely new level of control in the circadian system. Given the many and strong similarities between fungal and animal clocks, specifically including the conservation of regulatory architecture and components, understanding the function of a new family of proteins involved at the core of the circadian rhythm broadens the horizons of how we understand the clock mechanism. Identifying the specific role of this new player will tease out yet another level of awareness as to the sensitivity and response of the clock. Since the Neurospora clock is often used to understand the human clock, this could give us greater insight into our cycle and all of the implications that are associated with it, from ecology to human disease. PUBLIC HEALTH RELEVANCE: Given the many and strong similarities between fungal and animal clocks, understanding the function of a new family of proteins involved at the core of the circadian rhythm broadens the horizons of how we understand the clock mechanism (1). The effectiveness of medical treatment, sleep disorders, psychiatric disorders, cardiovascular disease, and cancer have all been linked to the rhythm of the circadian clock (2-6). Since the Neurospora clock is often used to understand the human clock, this could give us greater insight into our cycle and all of the implications that are associated with it.

描述(申请人提供)：昼夜节律是生物体的生化、生理或行为过程中大约24小时的循环，从动物到蓝藻都存在。昼夜节律被定义为具有大约一天的周期，可以在没有时间提示的情况下保持不变，同时保持被时间提示重置的能力，并且不受这些提示之外的信号的影响。脉孢子虫生物钟的核心组成蛋白包括频率(FRQ)、白领1(WC-1)、白领2(WC-2)和频率相互作用RNA解旋酶(FRH)。虽然前三个组成部分已经得到了很好的研究，但关于FRH在脉孢子虫生物钟功能中所扮演的角色，仍然存在许多问题。这项工作的目的是确定FRH在脉孢子虫昼夜节律时钟中的功能。为了研究这一机制，我将使用多方面的方法。在具体目标1中，我将识别对细胞生长和发育至关重要的FRH区域，并使用FRHR806H菌株将它们与与生物钟功能相关的区域区分开来；FRHR806H菌株是一种在保持菌株健康的同时，时钟的节律性被打乱的菌株。在具体目标2中，为了进一步了解FRH的功能和重要性，我将研究其他核心组成部分与FRH之间的相互作用，同时确定FRH对每一种相互作用的重要区域。在特定目标3中，我将确定FRH的RNA靶标，并探索其作为mRNA相互作用蛋白的作用，这一功能因其与DEAD盒蛋白家族，特别是DSHCT家族的同源性而被暗示。由于FRH与DEAD-box蛋白相似，因此断言FRH可能促进时钟控制的基因mRNAs与必要伙伴的相互作用是合乎逻辑的。这将证明生物钟系统的控制达到了一个全新的水平。鉴于真菌和动物时钟之间有许多强烈的相似之处，特别是包括调节结构和组成部分的保守，了解参与昼夜节律核心的新蛋白质家族的功能将拓宽我们理解时钟机制的视野。确定这个新玩家的具体角色将梳理出关于时钟的敏感度和反应的另一个级别的意识。由于脉孢子虫的生物钟经常被用来理解人类的生物钟，这可以让我们更好地了解我们的周期以及与之相关的所有含义，从生态学到人类疾病。 与公共健康相关：鉴于真菌和动物生物钟之间有许多和强烈的相似之处，了解参与昼夜节律核心的新蛋白质家族的功能将拓宽我们理解时钟机制的视野(1)。医疗、睡眠障碍、精神障碍、心血管疾病和癌症的有效性都与生物钟的节律有关(2-6)。由于脉孢子虫的时钟经常被用来理解人类的时钟，这可以让我们更好地了解我们的周期以及与之相关的所有含义。