Circadian rhythm regulation of blood-brain barrier transport and inflammation

Project Summary A challenge in targeting the neurologic drugs to the brain is the presence of the blood-brain barrier (BBB), a dynamic structure that prevents neurotoxic blood particles and pathogens from entering the brain while simultaneously regulating bidirectional transport of nutrients and waste products. Increasing our understanding of basic biology of the BBB is essential to improving existing therapies and finding new methods of targeting drugs to the brain. Previous work has found tight temporal regulation of the BBB by the molecular clock is necessary for efficient transport of xenobiotics from the brain; however, there has not been systemic characterization of the particles that are clock regulated nor do we have a good understanding of the regulation of this clock. We propose to characterize a robustly oscillating human BBB model using clonal human brain microvascular endothelial cells (BEC) with a circadian rhythm reporter and co-culture primary human astrocytes, pericytes and/or neurons in a 2D system. We hypothesize that secreted factors from pericytes and neurons are required for robust BEC rhythms, which regulate temporal gating of nutrients and proinflammatory cytokines. First, we will determine molecular and cellular components required for robust brain microvascular endothelial cell oscillation and the clock- dependent molecular trafficking through the BBB. Second, we will study the bidirectional effects of peripheral inflammation and BBB circadian rhythms. Ultimately, understanding timing of molecular trafficking through the BBB may provide candidate serum targets for chronomedicine and neurobiological treatments as well as generate insight into blood-effects on the brain.