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生物钟调节内源性神经递质的机制。 配体，其与睡眠和进食等行为的相关性，以及在 炎症的条件。我认为，除了外源性物质外排， BBB调节来自脑的颗粒的内吞作用（目的1）。根据已公布的和初步的 数据，我假设血脑屏障时钟通过转运蛋白调节的 内源性配体（目的2和3）。此外，我将询问炎症诱导的影响， 通过内毒素或睡眠剥夺对血脑屏障节律的影响（目的4）。为了实现这些目标， 我将使用分子测定（qPCR，细胞内离子测量， 代谢组学）、功能性生物测定（内吞作用、异生物质渗透性）和行为 睡眠（sleep），进食（feeding）该项目的成功完成将在以下方面取得重要进展： 了解BBB生物钟和行为。首先，了解分子 BBB时钟的机制将进一步定义时钟在门控血液进入大脑中的作用 通信其次，它将为行为监管提供新的见解。三是将 鉴定新内源性睡眠促进化合物。理解时间门控 在病理生理条件下，血脑屏障及其对行为的影响对于发展中国家来说是重要的。 采取措施改善人类健康。