Determine transporters at the blood-brain barrier relevant for homeostatic sleep

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Project Summary/Abstract Circadian clocks are ubiquitous in tissues, regulate many biological functions, and their misalignment or disruption contributes to deleterious health consequences. Although molecular underpinning of the circadian clock is well-studied, the role of the clock in tissue-specific biological functions, such as that of the blood-brain barrier (BBB), is poorly understood. The BBB is an interface between the vasculature and the brain that both protects the brain from peripheral insults and allows transports of endogenous molecules. Our recent work has found that the circadian clock regulates ATPase binding cassette transporter-mediated xenobiotic efflux from the brain. This proposal examines the mechanisms of BBB regulation of endogenous ligands and its relevance to behaviors such as sleep. Based on published and preliminary data, we hypothesize that the BBB clock influences behavior through transporter-regulated endogenous ligands. To pursue these aims, we will use a combination of molecular assays (qPCR, intracellular ion measurements, metabolomics) and behavioral sleep assays. Successful completion of this project will offer important advances in understanding the effects of the BBB transport and sleep. First, it will provide new insights into the regulation of sleep behavior. Second, it will identify novel endogenous sleep-promoting compounds. Understanding the temporal gating of the BBB and its effects on behavior under pathophysiologic conditions is important for developing interventions to improve human health.