Coordination of Circadian Physiology of Diverse Species

描述(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。这些节律共享许多形式和生化特性，增加了从蓝藻到人类的所有生物钟背后都有共同机制的可能性。在这个理论框架下，最初的P01基金提出，通过使用技术核心和共享数据方面的共同技术，可以在4个指导性模型系统中研究共同的过程：蓝藻聚球藻、真菌脉孢子菌、小鸡松果体和啮齿动物视交叉上核(SCN)。相反，研究发现，从蓝藻到哺乳动物和鸟类，所有的昼夜节律系统：(1)包含多个在某些实验条件下独立行为的昼夜节律振荡，并且由复杂的过程整合；(2)调节中间代谢和氧化还原状态作为时钟的下游过程，或许作为时钟机制本身的一部分；(3)从蛋白质合成和分解代谢的角度调节蛋白质动力学；(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)如果不考虑常见的蛋白质-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力学足够不同，不太可能在这些不同的模型系统之间建立深刻的进化关系。目前的建议试图通过将生物钟放在这些生物体的细胞机械、新陈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)细胞内和细胞之间的多种昼夜振荡机制是如何协调的？(2)代谢过程如何与这些系统中的时钟机械相互作用？(3)蛋白质动力学的调节如何适应昼夜节律组织的总体方案？(4)这些不同的生物体之间时钟的基本保守属性是什么？摘要：这项研究将引导我们用一种全面的系统生物学方法来研究生物钟，阐明与睡眠和清醒相关的时间生物学紊乱，其中许多都伴随着代谢、内分泌和细胞周期紊乱。

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.