Fundamental Mechanisms of Higher-Order Circadian Rhythms

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Abstract: Circadian clocks are a defining feature of living organisms. Rhythms originate from the molecular clocks of cells and propagate anatomically across the brain and body. A molecular understanding of the cooperation among 30 trillion individual clocks in the human body is a daunting yet important scientific challenge. Currently, much less is known of non-brain cell clocks, termed ‘peripheral clocks’ or ‘peripheral oscillators’. My research program aims to identify coordination mechanisms that enable higher-order (e.g., from cells to tissue) circadian rhythms and their physiological implications. To study clock function at the multi-oscillator level, we use molecular approaches and genetically defined cell and mouse models. We aim to achieve two goals specifically for this ESI MIRA R35 proposal. First, we will investigate how noisy, damped, and incomplete clock mechanisms within single cells combine to produce unified, precise, and robust rhythms at the organ-level. We will tease apart this coordination mechanism by applying single-cell methodologies and bioinformatic tools to quantify the behavior of individual hepatocyte oscillators under different liver rhythmicity states in vivo. Second, we will interrogate how rhythms are coupled across two peripheral organs. It is unclear how multiple tissue clocks synergize towards systemic-level control of daily homeostatic functions. Using a novel genetic mouse model that I have already constructed and validated, we will test the reciprocal influence between liver and skeletal muscle clocks and delineate the contribution of this axis to the biochemical makeup of the systemic circulation over circadian time. We will also determine how this axis is augmented by feeding-fasting behavior, a major brain-driven circadian cue. For both goals, we will focus on the identification of key molecular mediators and downstream homeostatic functions. The MIRA will afford us the ability to chase down the most impactful leads from these two areas and will allow me to dedicate more time to mentoring activities, an aspect of academic life that I am passionate about. My research program, based in circadian biology, provides a technically and conceptually rich training environment for graduate students and postdoctoral associates. As a whole, the proposed work will generate foundational knowledge of the complex inter-cellular interactions that generate rhythms. This knowledge is crucial for elucidating the molecular basis of rhythm disruption, an ever-growing occurrence in modern society. Circadian disruption is broadly linked with disease and thus understanding fundamental clock mechanisms offers insight into root causes of many human ailments. Likewise, the proposed studies will yield novel molecular targets aimed at counteracting rhythm disruption.