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

项目总结/摘要 生物钟在组织中普遍存在，调节许多生物功能，并且它们的生物钟是生物钟的一部分。 错位或中断会造成有害的健康后果。虽然分子 生物钟的基础已经得到了很好的研究，生物钟在组织特异性生物学中的作用 然而，对诸如血脑屏障（BBB）的功能的了解很少。BBB是一个 血管系统和大脑之间的界面，两者都保护大脑免受外周损伤 并允许内源性分子的运输。我们最近的研究发现， 时钟调节ATP酶结合盒转运蛋白介导的外源性物质从脑中流出。 本研究旨在探讨血脑屏障对内源性配体的调节机制， 与睡眠等行为相关。根据已公布的和初步的数据，我们 假设BBB时钟通过转运蛋白调节的内源性 配体。为了实现这些目标，我们将使用分子测定（qPCR，细胞内PCR）和免疫组织化学（ELISA）的组合。 离子测量、代谢组学）和行为睡眠测定。成功完成本 该项目将为理解BBB运输和睡眠的影响提供重要进展。 首先，它将为睡眠行为的调节提供新的见解。第二，它将识别小说 内源性睡眠促进化合物。了解BBB及其时间门控 在病理生理条件下对行为的影响对于开发干预措施非常重要， 改善人类健康。

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.