Circadian (daily) rhythms are a crucial component of human health that regulates sleep, alertness, hormones, metabolism, and many other biological processes. The fascination of this phenomenon is to explain how a biochemical mechanism (i) can robustly sustain a long period (~24 h) oscillation whose frequency keeps time so precisely, and (ii) enhance fitness in the natural environment. These questions remain critically important unanswered issues in the circadian rhythms field. For example, the adaptiveness is not clear for the most obvious circadian characteristic-a robust self-sustained oscillation in constant conditions. If """"""""anticipation"""""""" of future temporal events (e.g., dawn, dusk, etc.) is the goal of circadian timekeepers, why is a temperature-compensated """"""""hourglass timer"""""""" that is initiated by dawn or dusk not sufficient? And yet evolution in every case has selected an oscillator that sustains itself in non-natural continuous as the timekeeper for regulating daily processes, and this characteristic forms the core defining factor for circadian rhythms. The overall hypothesis of this project is that circadian pacemakers that are self-sustained in constant environments do provide a fitness advantage in cyclic environments and that multioscillator structure contributes to the maintenance of high amplitude oscillations in vivo. Testing this hypothesis will take advantage of the unique capabilities of the eubacteria Synechococcus elongatus (cyanobacterium) and E. coli by a three-pronged approach-genetic, biochemical, and by tests of adaptive fitness. First, the adaptive value of sustained circadian oscillations will be quantified y competition assays and metabolic patterns that correlate with adaptiveness will be identified as a """"""""signature"""""""" of the advantage conferred by sustained circadian oscillations. Second, the contributions of multioscillator organization will be assessed towards establishing (i) robust, sel-sustained oscillations, and (ii) adaptive competitiveness. Finally, a novel experimental selection approach will identify environmental pressures that can lead to the evolution of self-sustained circadian oscillations. The answers to these questions will help us to understand fundamental circadian organization and rhythmic regulation of metabolism;this understanding can help us to better design therapies for disorders in which circadian clocks are implicated.

Public Health Relevance

This project will clarify the organization of circadian systems at levels that were heretofore unreachable. Biological clocks have been found to be crucial for physical and mental health;cancer, metabolic disorders, cardiovascular disease, and depression are associated with the disruption of these timing systems by genetic and/or environmental disturbance (i.e., by shiftwork or jet-lag). Understanding the how and why of circadian organization ®ulation along with the development of therapies to properly phase sleep will allow us to enhance health, performance, and well-being of humans suffering from mental and/or metabolic disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Sesma, Michael A
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Egli, Martin; Johnson, Carl H (2015) Biochemistry that times the day. Biochemistry 54:104-9
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Johnson, Carl Hirschie; Egli, Martin (2014) Metabolic compensation and circadian resilience in prokaryotic cyanobacteria. Annu Rev Biochem 83:221-47
Yan, Yingjun; Jiang, Liwei; Aufderheide, Karl J et al. (2014) A microfluidic-enabled mechanical microcompressor for the immobilization of live single- and multi-cellular specimens. Microsc Microanal 20:141-51
Xu, Yao; Weyman, Philip D; Umetani, Miki et al. (2013) Circadian yin-yang regulation and its manipulation to globally reprogram gene expression. Curr Biol 23:2365-74
Ma, Peijun; Woelfle, Mark A; Johnson, Carl Hirschie (2013) An Evolutionary Fitness Enhancement Conferred by the Circadian System in Cyanobacteria. Chaos Solitons Fractals 50:65-74

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