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

项目摘要 哺乳动物生理和行为的每日定时是由生物钟系统协调的 在整个身体。这一系统的进化是为了帮助生物体将其行为与24小时的新陈代谢周期同步。 它在许多尺度上调节生理过程，从转录到转录， 每个细胞内的基因组对代谢稳态和睡眠-觉醒节律的影响。昼夜节律失调 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 昼夜节律系统是细胞自主的分子振荡器。通过过去几十年的英勇努力， 细胞自主时钟的许多分子成分和机制是已知的。然而，许多 但我们对人体内的生物钟如何协同工作以形成一个连贯的昼夜节律系统却知之甚少。 拟议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 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 工具，基于统计和数学建模，从昼夜节律中提取和整合知识， 从细胞到组织再到有机体的所有尺度的相关数据。借助这些计算工具，我们将 开发新的方法来测量单细胞和活体人体的昼夜节律系统，公开使用 研究哺乳动物昼夜节律系统的多组织组织结构，并使用数据 从电子医疗记录中探索昼夜节律系统和人类表型之间的联系。的 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，这项研究可以阐明并帮助我们开发昼夜节律和睡眠相关的治疗方法。 紊乱

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.