Interaction of Circadian Oscillators Within the Neurospora Cell

从细菌到人类的生物体都使用生物钟来控制日常的生化、生理和 行为节律。这种时钟会影响人类的生理，而正常时钟功能的中断可能会导致 健康问题，包括躁郁症和睡眠障碍。我们现在对这个问题有了一个明确的认识 构成昼夜节律计时系统核心的分子振荡器。然而，新的数据显示， 昼夜节律系统普遍比单个分子反馈环路振荡器更复杂， 明显的节奏感。现在有证据表明，在单个细胞内存在多个昼夜节律振荡器 微生物和多细胞生物体的细胞和组织之间。我们假设 不同的多个振荡器组成粗糙脉孢菌的时钟，这些振荡器相互联系 其他的则是为了产生细胞活动的协调节奏程序。我们已经鉴定出两种脉孢子虫 在没有FRQ/WC的情况下表现出昼夜节律的突变株(Light Mutant 1[LM1]和LM2) 振荡器(FWO)，以前被认为是真菌钟的核心。这些突变菌株揭示了一种 新的昼夜节律振荡器，被称为LMO，它可以在缺乏FWO的细胞中发挥作用，但这是耦合的 在系统完好无损的情况下发送到FWO。一个与所有时钟的组织相关的关键问题， 包括人类的时钟，是：多个振荡器如何相互通信以协调 调节昼夜节律？为了解决这个问题，我们将首先确定LM1和LM2的角色 LMO功能中的基因。第二，我们将使用遗传和物理方法来鉴定中央 LMO的组件。为了验证我们的假设，我们将确定LMO组件在物理上 与FWO的成员互动。此外，野生型细胞中的LMO成分将被灭活，以 确定LMO的丢失是否影响FWO的关键成分的表达和/或公开的节律性。至 描述LMO特定的输出，我们将使用转录图谱来识别有节奏的基因 在有功能的LMO，但缺乏FWO的细胞中表达。非专业总结：这些研究将 提供第二种细胞振荡器的第一个分子描述，并将通过以下方式揭示其机制 这些昼夜节律振荡器相互通信以协调控制节奏过程。此入站 TURN将促进治疗由昼夜节律失调引起的人类疾病的新方法。

Organisms from bacteria to humans use a circadian clock to control daily biochemical, physiological, and behavioral rhythms. This clock affects human physiology, and disruptions of normal clock function can cause health problems, including manic depression, and sleep disorders. We now have a firm understanding of the molecular oscillators that form the core of the circadian timing system. However, new data reveal that the circadian system is universally more complex than a single molecular feedback loop oscillator regulating all overt rhythmicity. Evidence now indicates that multiple circadian oscillators exist within single cells of microbial organisms and among the cells and tissues of multi-cellular organisms. We hypothesize that distinct multiple oscillators comprise the Neurospora crassa clock, and that these communicate with each other to generate a coordinated rhythmic program of cellular activities. We have identified two Neurospora mutant strains (Light Mutant 1 [LM1] and LM2) that display circadian rhythms in the absence of the FRQ/WC oscillator (FWO), previously considered to be the core of the fungal clock. These mutant strains uncover a novel circadian oscillator, called the LMO, which can function in cells that lack the FWO, but that is coupled to the FWO when the system is intact. A critical question that is relevant to the organization of all clocks, including the human clock, is: how do multiple oscillators communicate with each other to coordinately regulate circadian rhythms? To address this question, we will first determine the role of the LM1 and LM2 genes in the function of the LMO. Second, we will use genetic and physical methods to identify central components of the LMO. To test our hypothesis, we will determine if the LMO components physically interact with constituents of the FWO. In addition, LMO components will be inactivated in wild-type cells to determine if loss of the LMO affects the expression of key elements of the FWO and/or overt rhythmicity. To characterize LMO-specific outputs, we will use transcriptional profiling to identify genes that are rhythmically expressed in cells that have a functional LMO, but that lack the FWO. Lay Summary: These studies will provide the first molecular description of a second cellular oscillator, and will uncover the mechanisms by which circadian oscillators communicate with each other to coordinately control rhythmic processes. This in turn will facilitate new approaches for therapies for human conditions that result from circadian dysfunction.