A Multi-scale Approach to the Mammalian Circadian System and Its Role in Human Health and Disease - Administrative Supplement

项目摘要 哺乳动物生理和行为的日常时间由一套生物钟系统协调。 遍及全身。这个系统的进化是为了帮助生物体将它们的行为与24小时周期同步 它调节许多尺度上的生理过程，从转录的 每个细胞内的基因组与代谢动态平衡和睡眠-觉醒节律有关。昼夜节律失调 该系统与抑郁症和癌症等多种疾病有关。哺乳动物的基本单位 昼夜节律系统是一种细胞自主的分子振荡器。经过过去几十年的英勇努力， 细胞自主时钟的许多分子组成和机制是已知的。然而，很多 关于整个身体的生物钟如何协同工作来创造一个连贯的昼夜节律系统，我们知之甚少。 拟议的研究的长期目标是开发和应用新的工具来促进我们的理解 哺乳动物的昼夜节律系统以及该系统如何与环境和其他生理因素相互作用 影响人类健康和疾病的过程。我们研究的核心将是开发计算机 基于统计和数学建模的工具，从昼夜节律中提取和整合知识- 所有尺度的相关数据，从细胞到组织再到生物体。在这些计算工具的帮助下，我们将 开发在单细胞和活人中测量昼夜节律系统的新方法，公开使用 可获得的数据来研究哺乳动物昼夜节律系统的多组织组织，并使用数据 从电子病历中探索生理系统和人类表型之间的联系。这个 这项研究计划的成功将为昼夜节律社区带来广泛的资源。 最终，这项研究可以揭示并帮助我们开发与昼夜节律和睡眠相关的治疗方法 精神错乱。

Project Summary The daily timing of mammalian physiology and behavior is coordinated by a system of circadian clocks throughout the body. This system evolved to help organisms synchronize their behavior to the 24-h cycle of night and day, and it regulates physiological processes across many scales, from the transcription of the genome inside each cell to metabolic homeostasis and the sleep-wake rhythm. Dysregulation of the circadian system is linked to diverse conditions such as depression and cancer. The basic unit of the mammalian circadian system is a cell-autonomous, molecular oscillator. Through heroic efforts of the last few decades, many of the molecular components and mechanisms of the cell-autonomous clock are known. However, much less is known about how the clocks throughout the body work together to create a coherent circadian system. The long-term goal of the proposed research is to develop and apply new tools to advance our understanding of the mammalian circadian system and how the system interacts with the environment and other physiological processes to influence human health and disease. The core of our research will be to develop computational tools, based on both statistical and mathematical modeling, to extract and integrate knowledge from circadian- related data at all scales, from cells to tissues to organisms. Aided by those computational tools, we will develop new methods to measure the circadian system in single cells and in living humans, use publicly available data to investigate the multi-tissue organization of the mammalian circadian system, and use data from electronic medical records to explore the link between the circadian system and human phenotypes. The success of this research program will lead to a broad array of resources for the circadian community. Ultimately, this research could shed light on and help us develop treatments for circadian- and sleep-related disorders.