The rotation of the Earth subjects terrestrial organisms to daily light/dark cycles. To keep in sync with these geophysical oscillations, we have evolved a biological timing system that segregates our behavior, physiology, and metabolism with circadian – or nearly 24 hour (from circa diem, ‘about a day’) – rhythmicity. The circadian timekeeping system is a prediction mechanism that synchronizes internal organismal state with the external environment. While the central clock resides in the brain, all our cells have circadian clocks. Disruption of circadian rhythms is extraordinarily common in modern society and has been linked with neurological disease, metabolic disease, cancer, and aging. Our research seeks to understand the fundamental relationships between the circadian clock and diseases of the developing brain. We have identified the core circadian clock protein BMAL1 as a regulator of protein synthesis (i.e. translation) (Cell, 2015). BMAL1 promotes circadian rhythms in protein synthesis as a substrate of the mechanistic target of rapamycin (mTOR) pathway, a critical gauge of nutritive status and stress. We have characterized a novel, potentially modifiable link between the circadian timing system and cellular signaling.
One of our major goals is the identification of the mechanisms of circadian-regulated protein synthesis in neural and non-neural cells. How are rhythms of protein synthesis generated? How does protein synthesis coordinate circadian timekeeping? What is the signaling logic that dictates which proteins are made at which time of day? How do circadian rhythms affect protein synthesis in neurons? How do circadian clocks in the brain impact neural function at the molecular and behavioral level? How are these mechanisms disrupted in neurological disease models?
We utilize and develop animal models, cell-based reporter assays, live cell imaging, behavioral assays, and biochemistry to address fundamental questions of circadian timing, translation, and neurological function with our gaze focused on diseases of the nervous system.