Intercellular communication modulates blood brain barrier integrity

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Diseases affecting the central nervous system are some of the most poorly treatable due to the difficulty in delivering drugs across the blood brain barrier (BBB). The BBB is a dynamic barrier between, which tightly regulates the influx of molecules to the brain, in order to protect the brain from potentially blood borne pathogens and guarantee maintenance of a tight homeostasis. Furthermore, alterations in BBB function have been found in some neurodegenerative diseases although mechanism are largely not elucidated. Recent studies have shown that some of the features of the BBB, i.e., drug efflux transporters, are modulated by the biological clock synchronising most physiological processes to the environmental day/night cycles. This means that throughout a 24-hour day, the ability of a drug to cross BBB and reach a target in the brain is fluctuating. This has obvious implications both, to increase treatment efficacy and reduce off-target toxicity. Using an advanced tri-culture in vitro model consisting of all cell types typically considered part of the BBB, i.e., endothelial cells, pericytes and astrocytes, we have previously shown that in addition to drug transporters also the permeability of the tight junctions between brain endothelial cells is regulated by the circadian clock. Surprisingly, even if the clock in the endothelial cells is disrupted, the pericytes and/or astrocytes in the co-culture can rescue rhythmicity in endothelial cell mediated rhythms in BBB tightness. Here, we will investigate the underlying mechanism for inter-cellular communication between these cell types. We will make use of established BBB tri-culture models and real-time reporter methods available in the Chrono group at Warwick and complementary expertise in inter-cellular communication from the Vatish Group at Oxford University. Not only would understanding inter-BBB communication be important to circadian control of BBB tightness, but also further the understanding of pathological alterations in BBB tightness in neurodegenerative as well as other diseases.