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每天的生化、生理和代谢。 行为节奏这种生物钟会影响人体的生理机能，正常生物钟功能的中断会导致 健康问题，包括躁狂抑郁症和睡眠障碍。我们现在对 分子振荡器构成了昼夜节律计时系统的核心。然而，新的数据显示， 昼夜节律系统普遍比调节所有生理节律的单个分子反馈回路振荡器更复杂。 明显的节奏感现在的证据表明，多个昼夜节律振荡器存在于单个细胞内， 微生物有机体之间以及多细胞有机体的细胞和组织之间。我们假设 不同的多个振荡器组成了粗糙脉孢菌的时钟，这些振荡器与每个振荡器进行通信。 另一种是产生细胞活动的协调节律程序。我们已经鉴定出两种脉孢菌 突变株（Light Mutant 1 [LM 1]和LM 2），在缺乏FRQ/WC的情况下显示昼夜节律 振荡器（FWO），以前被认为是真菌时钟的核心。这些突变菌株揭示了 一种新的昼夜节律振荡器，称为LMO，它可以在缺乏FWO的细胞中发挥作用，但它与FWO相耦合。 在系统完好的情况下发送给FWO一个与所有时钟的组织有关的关键问题， 包括人类的时钟，是：如何多个振荡器相互沟通，以协调 调节昼夜节律为了解决这个问题，我们将首先确定LM 1和LM 2的作用 基因在LMO中的作用第二，我们将使用遗传和物理方法来确定中央 LMO的组成部分。为了验证我们的假设，我们将确定LMO组件的物理 与FWO的成分相互作用。此外，LMO组分将在野生型细胞中失活， 确定LMO的丧失是否影响FWO的关键要素的表达和/或明显的节律性。到 为了表征LMO特异性输出，我们将使用转录谱来识别有节奏的基因， 在具有功能性LMO但缺乏FWO的细胞中表达。摘要：这些研究将 提供了第二个细胞振荡器的第一个分子描述，并将揭示机制， 这些昼夜节律振荡器相互通信以协调地控制节律过程。这 turn将促进治疗由昼夜节律功能障碍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.