CBE Julian C. Smith Lectureship (pt. 2)

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Description

Controlling Biological Time A property of particular interest in systems biology is the robustness of a biophysical network: the ability to maintain some target level of behavior or performance in the presence of uncertainty and/or perturbations. For the past 20 years, our group has studied the circadian clock as a model system for closed-loop robust timekeeping. Rhythms that emerge at the gene regulatory level maintain coherence through signaling across thousands of neuronal oscillators in the hypothalamus. Synchronized behavior emerges from the networked control properties, despite the relatively “sloppy” behavior of individual components (cells). In recent years, our attention has shifted from the analysis of natural control mechanisms in the clock to the design of “forcing” or control protocols that allow for rapid re-entrainment of the clock. Maintaining robust circadian rhythms has been linked to longevity and metabolic health. Because these rhythms are disturbed by factors such as jet lag, shift work, and high-fat diets, there is interest in developing pharmacological control strategies to modulate circadian function. The design of therapeutic strategies is currently limited by the lack of a clear mechanistic understanding of interactions between posttranslational regulators, as efficient control of clock behavior will likely require several simultaneous modulations. Although small molecules that modulate clock function might offer therapeutic approaches to such diseases, only a few compounds have been identified that selectively target core clock proteins. Using mathematical modeling and systems biology approaches, we provide a mechanistic interpretation for the relationship between candidate regulators, lending insight into circadian regulation and potential chronotherapies.