Metabolic control of the molecular clock

The molecular clock and circadian rhythm are known to control metabolism, but does the molecular clock respond to metabolic cues?  Does metabolic input feed back to control the molecular clock?  This question is particularly important in the context of cancer, as new therapies targeting altered cancer cell metabolism are currently in clinical trial and due to enter the clinic soon.  In particular, we are interested in the role of the amino acid glutamine in controlling the molecular clock.  Glutamine uptake and catabolism are increased in many cancers, particularly those driven by MYC, and glutamine metabolism in cancer is currently the subject of several clinical and preclinical therapies (Altman et al, Nature Reviews Cancer, 2016).

We will study the effect of glutamine deprivation on the molecular clock.  The key questions stemming from this work will be: is the clock disrupted, does this connect with stress responses that may occur in the absence of glutamine, and do these changes in the molecular clock machinery allow for a survival advantage in metabolic stress?  These studies will both reveal a fundamental node of control of the molecular clock, and begin to reveal how cancer cells under metabolic stress from therapy may alter the circadian machinery for their advantage.

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