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

基本信息

批准号：
10891961
负责人：
Shirley Zhang
金额：
$ 1.45万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10891961
关键词：
ATP phosphohydrolase Affect 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 Probability Publishing Regulation Role Satiation Signal Transduction Sleep Sleep Deprivation Steroids Structure Tissues Vitamin E Vitamin K Vitamins Work Xenobiotics access restrictions 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 systemic inflammatory response transmission process

项目摘要

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。