Circadian clocks play important roles in many aspects of mammalian physiology including glucose, drug, and tumor metabolism. At the molecular level, mammalian clocks consist of a network of transcription factors: CLOCK and BMAL1 drive expression of period (PER) and cryptochrome (CRY) proteins, which in turn inhibit CLOCK:BMAL1, resulting in oscillating transcription of genes regulated by CLOCK:BMAL1, including Per1-3 and Cry1-2.  Circadian clocks are widely distributed in mammalian tissues and control the transcription of a large number of genes in every organ that has been examined thus far.  The timing of clocks in peripheral organs is set by metabolic cues, including AMPK-dependent phosphorylation of cryptochromes. The discovery of clocks in peripheral organs has led to intense interest in their physiological functions outside of the central nervous system where clocks drive behavioral rhythms.  In the Lamia Lab at Scripps Research, we are dissecting the mechanisms by which circadian clocks, in particular the circadian repressors CRY1 and CRY2, regulate exercise physiology and cancer using a combination of genetics and molecular and cell biology.

Current Projects:

1.Circadian regulation of exercise physiology:

We demonstrated that CRY1 and CRY2 repress other transcription factors in addition to CLOCK and BMAL1, including several nuclear hormone receptors (NRs). CRY1 and CRY2 interact with NRs, and repress their transcriptional activity (Kriebs et al., 2017).  Among the NRs suppressed by CRYs is the peroxisome proliferator activated receptor delta (PPARd), an important regulator of exercise physiology.

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