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。 该提案研究了内源性 BBB 昼夜节律时钟调节机制 配体，其与睡眠和进食等行为的相关性，及其扰动 炎症的情况。我建议除了外源物质外流之外，生物钟 BBB 调节大脑颗粒的内吞作用（目标 1）。根据已发布的和初步的 数据，我假设 BBB 时钟通过转运蛋白调节影响行为 内源配体（目标 2 和 3）。此外，我将询问炎症诱发的影响 内毒素或睡眠剥夺对 BBB 节律的影响（目标 4）。为了实现这些目标， 我将结合使用分子检测（qPCR、细胞内离子测量、 代谢组学）、功能生物测定（胞吞作用、异生素渗透性）和行为 化验（睡眠、进食）。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时钟机制将进一步明确时钟在控制血液流向大脑中的作用 沟通。其次，它将为行为监管提供新的见解。第三，它将 识别新型内源性促进睡眠的化合物。了解时间门控 BBB 及其在病理生理条件下对行为的影响对于发育很重要 改善人类健康的干预措施。