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

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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.