Intercellular communication modulates blood brain barrier integrity

影响中枢神经系统的疾病是一些最难治疗的疾病，因为药物很难通过血脑屏障（BBB）。血脑屏障是一种动态屏障，它严格调节分子流入大脑，以保护大脑免受潜在的血源性病原体的侵害，并保证维持严密的体内平衡。此外，在一些神经退行性疾病中发现血脑屏障功能的改变，但其机制在很大程度上尚未阐明。最近的研究表明，血脑屏障的一些特征，即药物外溢转运体，是由生物钟调节的，生物钟将大多数生理过程与环境昼夜周期同步。这意味着在一天的24小时内，药物穿过血脑屏障并到达大脑目标的能力是波动的。这对提高治疗效果和减少脱靶毒性都有明显的意义。使用先进的三培养体外模型，包括通常被认为是血脑屏障一部分的所有细胞类型，即内皮细胞、周细胞和星形胶质细胞，我们之前已经表明，除了药物转运蛋白外，脑内皮细胞之间紧密连接的通透性也受到生物钟的调节。令人惊讶的是，即使内皮细胞中的时钟被破坏，共培养中的周细胞和/或星形胶质细胞也可以挽救内皮细胞介导的血脑屏障紧密性的节律性。在这里，我们将研究这些细胞类型之间细胞间通讯的潜在机制。我们将利用华威大学Chrono团队已建立的BBB三培养模型和实时报告方法，以及牛津大学Vatish团队在细胞间通信方面的互补专业知识。了解血脑屏障间的通讯不仅对血脑屏障紧密度的昼夜节律控制很重要，而且对进一步了解神经退行性疾病及其他疾病中血脑屏障紧密度的病理改变也很重要。

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.