Coordination of Circadian Physiology of Diverse Species

描述（由申请人提供）：昼夜节律是发生在不同生物体中的生理功能的内源性振荡。这些节律具有许多共同的形式和生物化学特性，这提高了从蓝藻到人类的所有生物钟的共同机制的可能性。在这个理论框架下，最初的P01基金提出，通过在技术核心和共享数据中使用通用技术，可以在4个指导性模型系统中研究一个通用过程：蓝藻聚球藻，真菌脉孢菌，小鸡松果体和啮齿动物视交叉上核（SCN）。相反，研究表明，从蓝细菌到哺乳动物和鸟类，所有昼夜节律系统：（1）包括多个昼夜节律振荡，这些振荡在某些实验条件下独立表现，并通过复杂的过程整合;（2）调节中间代谢和氧化还原状态作为时钟的下游过程，也许也是时钟机制本身的一部分;（3）在蛋白质合成和催化剂方面调节蛋白质动力学;（4）将翻译后调节作为规则而不是例外，因此转录/翻译环模型不足以解释时钟。此外，数据告诉我们，已知振荡器组件的同源性并不是一个共同的元素：（1）如果不考虑共同的蛋白质-蛋白质相互作用基序，已知时钟基因的序列是非常不同的;（2）时钟基因转录和翻译的时间动态是完全不同的，这些不同的模型系统之间的深层进化关系是不可能的。目前的建议试图通过将生物钟置于这些生物体的细胞机制，代谢和蛋白质动力学的背景下来扩展这些发现。我们将问：（1）细胞内和细胞间的多种昼夜节律振荡机制是如何协调的？(2)在这些系统中，新陈代谢过程是如何与生物钟机制相互作用的？(3)蛋白质动力学的调节如何与昼夜节律组织的总体方案相适应？以及（4）在这些不同的生物体中，生物钟的基本保守特性是什么？简单总结：这项研究将引领一种全面的系统生物学方法来研究生物钟，阐明与睡眠和觉醒相关的时间生物学紊乱，其中许多都与代谢，内分泌和细胞周期紊乱有关。

DESCRIPTION (provided by applicant): Circadian rhythms are endogenous oscillations of physiological functions that occur in diverse organisms. These rhythms share many formal and biochemical properties, raising the possibility that common mechanisms underlie all circadian clocks from cyanobacteria to humans. With this theoretical framework, the original P01 grant proposed that, by using common technologies in technical cores and shared data, a common process could be studied in 4 instructive model systems: the cyanobacterium Synechococcus, the fungus Neurospora, the chick pineal gland, and the rodent suprachiasmatic nucleus (SCN). The research instead revealed that all circadian systems, from cyanobacteria to mammals and birds: (1) comprise multiple circadian oscillations that behave independently under some experimental conditions and are integrated by complex processes; (2) regulate intermediary metabolism and redox state as both downstream processes of the clock and perhaps as part of the clock mechanism itself; (3) regulate protein dynamics in terms of both protein synthesis and catabolism; and (4) incorporate post-translational regulation as the rule rather than the exception, such that transcription/translation loop models are not sufficient to explain the clock. Further, the data told us that homology of known oscillator components is not a common element: (1) The sequences of known clock genes are very different if one discounts common protein-protein interaction motifs; (2) The temporal dynamics of clock gene transcription and translation are disparate enough that a deep evolutionary relationship among these diverse model systems is unlikely. The present proposal seeks to extend these findings by placing the circadian clock in the context of these organisms' cellular machinery, metabolism, and protein dynamics. We will ask: (1) How are multiple circadian oscillatory mechanisms coordinated within and among cells?; (2) How do metabolic processes interact with clock machinery in each of these systems?; (3) How does the regulation of protein dynamics fit into the overall scheme of circadian organization?; and (4) What are the fundamentally conserved properties of the clocks among these diverse organisms? Lay summary: This research will lead the way to a comprehensive systems biology approach to biological clocks that will elucidate chronobiological disorders associated with sleep and wakefulness, many of which are attended by metabolic, endocrine, and cell-cycle disorders.