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

确定与稳态睡眠相关的血脑屏障转运蛋白

• 批准号: 10548484
• 负责人: Shirley Zhang
• 金额: $ 2.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548484
• 关键词: ATP phosphohydrolase; Address; Affect; Alpha Rhythm; Animal Behavior; Behavior; Behavioral; Binding; Biological Assay; Biological Process; Blood - brain barrier anatomy; Brain; Cells; Cerebrovascular Disorders; Chronic; Chronotherapy; Circadian Rhythms; Data; Disease model; Drosophila genus; Endothelium; Event; Future; Goals; Health; Human; Impairment; Inflammatory; Intervention; Ions; Ligands; Mammals; Measurement; Measures; Mediating; Metabolic syndrome; Molecular; Mus; Nervous System Physiology; Neurophysiology - biologic function; Obesity; Organism; Periodicity; Peripheral; Permeability; Publishing; RNA Interference; Regulation; Role; Sleep; Sleep Deprivation; Stimulus; Structure; Tissues; Vitamins; Work; Xenobiotics; base; behavior influence; blood-brain barrier permeabilization; circadian; circadian pacemaker; improved; insight; knock-down; lipophilicity; metabolomics; molecular clock; mouse model; mutant; novel; parent grant; sleep behavior; sleep regulation; systemic inflammatory response

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.

项目概要/摘要 生物钟在组织中普遍存在，调节许多生物功能，其 失调或破坏会导致有害的健康后果。虽然分子 生物钟的基础已得到充分研究，生物钟在组织特异性生物钟中的作用 人们对血脑屏障（BBB）等功能知之甚少。 BBB 是一个 脉管系统和大脑之间的界面，保护大脑免受外周损伤 并允许内源分子的运输。我们最近的工作发现，昼夜节律 时钟调节 ATP 酶结合盒转运蛋白介导的异生物质从大脑的流出。 该提案研究了内源配体的 BBB 调节机制及其 与睡眠等行为的相关性。根据已发布的初步数据，我们 假设 BBB 时钟通过转运蛋白调节的内源性影响行为 配体。为了实现这些目标，我们将结合使用分子检测（qPCR、细胞内 离子测量、代谢组学）和行为睡眠测定。顺利完成本次 该项目将为理解血脑屏障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。其次，它会识别小说 内源性促进睡眠的化合物。了解 BBB 的时间门控及其 对病理生理条件下行为的影响对于制定干预措施非常重要 改善人类健康。