Circadian clocks play important roles in many aspects of mammalian physiology including glucose homeostasis, xenobiotic metabolism, immune function, and tumor formation. 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 The Scripps Research Institute, we are dissecting the mechanisms by which circadian clocks regulate metabolic physiology and cellular proliferation and transformation, the molecular mechanisms by which cryptochromes regulate transcription, and their ability to mediate circadian clock output pathways using a combination of mouse genetics, molecular and cell biology and biochemistry.

Current Projects:

1.Cryptochrome regulation of nuclear hormone receptors:

We hypothesized that CRY1 and CRY2 may repress other transcription factors in addition to CLOCK and BMAL1, and initially examined a large family of master metabolic regulators, the nuclear hormone receptors (NRs).  We have found that CRY1 and CRY2 physically interact with several mammalian NRs, including the steroid hormone receptors.  We are using cells and tissues derived from wildtype and Cry1-/-;Cry2-/- mice to study the role of cryptochromes in transcriptional regulation by NRs and analyzing related aspects of physiology in Cry1-/-;Cry2-/- mice with a particular focus on drug metabolism and exercise physiology.