Determining the importance of temporal regulation of the blood-brain barrier

确定血脑屏障时间调节的重要性

• 批准号: 10445428
• 负责人: Shirley Zhang
• 金额: $ 24.9万
• 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/10445428
• 关键词: ATP phosphohydrolase; Address; Affect; Alpha Rhythm; Animal Behavior; Animals; Behavior; Behavioral; Behavioral Assay; Binding; Biological Assay; Biological Process; Blood; Blood - brain barrier anatomy; Brain; Chronotherapy; Circadian Rhythms; Communication; Data; Drosophila genus; Endocytosis; Endotoxins; Event; Goals; Health; Hormones; Human; Hunger; Impairment; Inflammation; Inflammatory; Intervention; Ions; Ligands; Mammals; Measurement; Mediating; Mentors; Metabolic syndrome; Modeling; Molecular; Mus; Mutation; Nervous System Physiology; Neurophysiology - biologic function; Obesity; Organism; Pathway interactions; Periodicity; Peripheral; Permeability; Phase; Publishing; Regulation; Role; Satiation; Signal Transduction; Sleep; Sleep Deprivation; Structure; Time; Tissues; Vitamin E; Vitamin K; Vitamins; Work; Xenobiotics; base; behavior influence; blood-brain barrier disruption; blood-brain barrier permeabilization; circadian; circadian pacemaker; circadian regulation; feeding; fly; improved; insight; lipophilicity; metabolomics; molecular clock; mouse model; mutant; novel; particle; steroid hormone; systemic inflammatory response; transmission process

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 circadian clock regulation of endogenous ligands, its relevance to behaviors such as sleep and feeding, and its perturbation under conditions of inflammation. I propose that in addition to xenobiotic efflux, the circadian clock in the BBB regulates endocytosis of particles from brain (Aim 1). Based on published and preliminary data, I hypothesize that the BBB clock influences behavior through transporter-regulated endogenous ligands (Aim 2 and 3). Further, I will interrogate the effect of inflammation induced by either endotoxin or sleep deprivation on the rhythms of the BBB (Aim 4). To pursue these aims, I will use a combination of molecular assays (qPCR, intracellular ion measurements, metabolomics), functional bioassays (endocytosis, xenobiotic permeability) and behavioral assays (sleep, feeding). Successful completion of this project will offer important advances in understanding both the BBB circadian clock and behavior. First, understanding molecular mechanism of the BBB clock will further define the role of the clock in gating blood to brain communication. Second, it will provide new insights into the regulation of behavior. Third, 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.

项目摘要/摘要 昼夜节律在组织中无处不在，调节许多生物学功能及其 未对准或中断会导致有害的健康后果。虽然分子 昼夜节律的基础是研究的，时钟在组织特异性生物学中的作用 众所周知的功能，例如血脑屏障（BBB）的功能。 BBB是 脉管系统与大脑之间的界面都保护大脑免受周围侮辱 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ATPase结合盒式转运蛋白介导的脑介导的异种外排。 该提案检查了内源性BBB昼夜节律调节的机制 配体，与睡眠和喂养等行为的相关性及其在下面的扰动 炎症条件。我建议，除了异生物外排之外，昼夜节律时钟 BBB调节大脑颗粒的内吞作用（AIM 1）。基于出版和初步 数据，我假设BBB时钟通过转运器调节影响行为 内源配体（AIM 2和3）。此外，我将询问引起的炎症的影响 通过内毒素或睡眠剥夺BBB的节奏（AIM 4）。追求这些目标， 我将使用分子测定的组合（QPCR，细胞内离子测量， 代谢组学），功能性生物测定（内吞作用，异种生物渗透性）和行为 测定（睡眠，进食）。成功完成该项目将为 了解BBB昼夜节律的时钟和行为。首先，了解分子 BBB时钟的机制将进一步定义时钟在门控血向大脑中的作用 沟通。其次，它将为行为调节提供新的见解。第三，它将 识别新型的内源性睡眠促进化合物。了解 BBB及其对病理生理状况下行为的影响对于发展很重要 改善人类健康的干预措施。