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内的生理功能的内源性振荡。这些节律具有许多形式和生化特性，提高了从蓝藻到人类的所有生物钟的共同机制的可能性。在这一理论框架下，最初的P01基金提出，通过技术核心中的共同技术和共享数据，可以在蓝藻聚球菌、真菌神经孢子菌、鸡松果体和啮齿动物视交叉上核（SCN） 4个具有指导意义的模型系统中研究一个共同的过程。研究表明，从蓝藻到哺乳动物和鸟类，所有的昼夜节律系统：(1)包括多个昼夜节律振荡，这些振荡在某些实验条件下表现独立，并通过复杂的过程整合；(2)调节中间代谢和氧化还原状态，它们既是生物钟的下游过程，也可能是生物钟机制本身的一部分；(3)从蛋白质合成和分解代谢两方面调节蛋白质动力学；(4)将翻译后调控作为规则而非例外，这样转录/翻译循环模型就不足以解释生物钟。此外，数据告诉我们，已知振荡器组分的同源性不是一个共同的因素：(1)如果一个人忽略了共同的蛋白质-蛋白质相互作用基序，已知时钟基因的序列就会非常不同；(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不太可能存在深层的进化关系。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)多种昼夜节律振荡机制如何在细胞内部和细胞之间协调？(2)在这些系统中，代谢过程如何与时钟机制相互作用？(3)蛋白质动态调节如何适应昼夜节律组织的整体方案？(4)在这些不同的生物中，时钟的基本保守特性是什么？总结：这项研究将为生物钟的全面系统生物学方法开辟道路，该方法将阐明与睡眠和觉醒相关的时间生物学紊乱，其中许多是由代谢、内分泌和细胞周期紊乱引起的。

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.