Fundamental properties of circadian rhythms

Project Summary Molecular mechanisms of circadian rhythms generate autonomous oscillations that process external time cues (e.g., light/dark cycles) that align temporal organizations of cellular and physiological processes to external environments maximizing the survival of organisms. Defective or misaligned circadian rhythms correlate with human diseases ranging from sleep disorders to cancer. The molecular circuitry of circadian rhythms involves transcriptional and translational feedback loops (TTFL), which generate autonomous oscillations of about 24 hours and subsequently regulate rhythmic cellular and physiological events (e.g., timing of cell divisions, bowel movements, body temperature, etc.). In the past three decades, extensive efforts have been made by numerous circadian biologists to identify core clock genes and their transcriptional, post-transcriptional, and post-translational mechanisms that create a time-delayed negative feedback loop. However, detailed molecular mechanisms that determine the period of circadian rhythms and align the phase of the internal clock to external perturbations remain largely unknown. In the proposed project, we will combine mathematical modeling, statistical uncertainty quantification methods, and experimental validations to determine molecular mechanisms that determine the circadian period and light-dependent phase shift of circadian rhythms. Successful completion of the proposed project will lead to potential strategies to control, rescue, and phase shift circadian rhythms for chronotherapeutic applications.