Sleep and Circadian Rhythm Disorders After Traumatic Brain Injury

脑外伤后的睡眠和昼夜节律紊乱

• 批准号: 10799966
• 负责人: Annika Fitzpatrick Barber
• 金额: $ 42.36万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10799966
• 关键词: Ablation; Acute; Affect; Animal Model; Arousal; Autophagocytosis; Behavior; Behavioral; Behavioral Assay; Behavioral Genetics; Blood - brain barrier anatomy; Brain; Cellular biology; Cessation of life; Chronic; Circadian Dysregulation; Circadian Rhythm Sleep Disorders; Circadian Rhythms; Complex; Data; Data Set; Defect; Disease; Drosophila genus; Drosophila melanogaster; Endocrine System Diseases; Feedback; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Models; Goals; Head; Health; Human; Immunomodulators; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Investigation; Knock-out; Link; Longevity; Mediating; Mediator; Metabolic; Metabolic Diseases; Modeling; Molecular; Mood Disorders; Motor; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Outcome; Oxidative Stress; Pathology; Pathway interactions; Patients; Periodicity; Persons; Phase; Physiological; Post-Traumatic Stress Disorders; Prevalence; Process; Publishing; Quality of life; RNA interference screen; Recovery; Reporting; Risk; Role; Sleep; Sleep Architecture; Sleep Fragmentations; Sleep disturbances; Survivors; System; TBI Patients; Testing; Therapeutic Intervention; Tissues; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States; base; chronic traumatic encephalopathy; circadian; circadian regulation; design; disability; fly; follow-up; gene discovery; gene function; genetic manipulation; improved; improvement on sleep; injury-related death; knock-down; mild traumatic brain injury; molecular marker; mortality; multicatalytic endopeptidase complex; nervous system disorder; neuropsychiatric disorder; novel; pharmacologic; prevent; response; response to injury; sex; sleep regulation; tool; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Almost two million people sustain a traumatic brain injury (TBI) in the United States every year. TBI is a contributing factor to one-third of all injury-related deaths, and more than 40% of survivors suffer long-term impairments, including sleep and circadian rhythm disorders (SCRDs). These disorders may underlie or exacerbate the lifetime elevated risks of metabolic disorders, mood disorders, and neurodegenerative disease found in TBI patients. While the prevalence of SCRDs has long been recognized in TBI patients and recapitulated in animal models, the mechanisms underlying these disorders at the molecular and circuit levels are unknown. This proposal exploits the Drosophila melanogaster genetic model to identify genes that contribute to TBI-induced SCRDs and to determine the role of sleep in mediating molecular and physiological outcomes of TBI. Based on published and preliminary data, we hypothesize that TBI-induced inflammatory responses disrupt the circadian and sleep regulatory systems in the brain, forming a positive feedback loop that prolongs inflammation. We have established a tunable, head-specific Drosophila TBI paradigm that results in chronic sleep reduction and reduced circadian rhythmicity of locomotor behavior after injury. In this model, mild injury induces SCRD without affecting mortality. We seek to answer two key questions: (Aim 1) What are the genetic drivers of sleep and circadian remodeling at various phases after TBI? (Aim 2) Can interventions that target sleep and circadian disruption after injury improve TBI outcomes? In Aim 1 we will conduct a candidate knockdown/knockout screen of proinflammatory genes to identify genes that contribute to aspects of sleep and circadian disruption after injury. In Aim 2 we will conduct the first comprehensive analysis of sleep architecture changes after TBI in both sexes of flies. We will use this data to design a paradigm of sleep manipulation at various phases after TBI to examine how sleep changes after TBI affect longevity, locomotor function, and neuronal and glial health. To pursue these aims, I will combine genetic tools for physiological characterization and for sleep manipulation as well a behavioral assays available in the fly model. Use of a novel Drosophila TBI model will allow unparalleled temporally and spatially controlled genetic manipulations to identify not only which genes are important in SCRDs, but in what tissue(s) they act. The proposed study will be impactful as it will define genetic pathways that link fundamental brain processes to TBI and provide the foundation for future investigation with translational implications.

项目概要/摘要 在美国，每年有近 200 万人遭受创伤性脑损伤 (TBI)。 TBI 是导致所有伤害相关死亡的三分之一、超过 40% 的原因之一。 幸存者遭受长期损害，包括睡眠和昼夜节律紊乱 （SCRD）。这些疾病可能会导致或加剧终生代谢性疾病风险升高 TBI 患者中发现的疾病、情绪障碍和神经退行性疾病。虽然 SCRDs 在 TBI 患者中的患病率早已被认识到，并且在动物中也得到了重现 模型中，这些疾病在分子和电路水平上的潜在机制是 未知。该提案利用果蝇遗传模型来识别 有助于 TBI 诱导 SCRD 并确定睡眠在疾病中的作用的基因 介导 TBI 的分子和生理结果。基于已发布和 根据初步数据，我们假设 TBI 诱导的炎症反应扰乱了昼夜节律 和大脑中的睡眠调节系统，形成正反馈循环，延长睡眠时间 炎。我们已经建立了一个可调节的、头部特异性的果蝇 TBI 范式 导致长期睡眠减少和运动行为的昼夜节律性降低 受伤。在此模型中，轻度损伤会诱发 SCRD，但不会影响死亡率。我们寻求答案 两个关键问题：（目标 1）睡眠和昼夜节律重塑的遗传驱动因素是什么 TBI 后的各个阶段？ （目标 2）可以针对睡眠和昼夜节律紊乱进行干预吗 受伤后可以改善 TBI 结局吗？在目标 1 中，我们将进行候选人击倒/淘汰赛 筛选促炎症基因，以确定有助于睡眠和睡眠等方面的基因 受伤后昼夜节律紊乱。在目标 2 中，我们将进行第一次全面分析 TBI 后两性果蝇的睡眠结构发生变化。我们将使用这些数据来设计一个 TBI 后各个阶段的睡眠操纵范例，以检查 TBI 后睡眠如何变化 TBI 影响寿命、运动功能以及神经元和神经胶质的健康。为了实现这些目标，我 将结合用于生理特征和睡眠操纵的遗传工具以及 苍蝇模型中可用的行为测定。使用新型果蝇 TBI 模型将允许 无与伦比的时间和空间控制的基因操作不仅可以识别哪些 基因在 SCRD 中很重要，但它们在哪些组织中发挥作用。拟议的研究将是 具有影响力，因为它将定义将基本大脑过程与 TBI 联系起来的遗传途径 为未来具有转化意义的研究奠定基础。

项目成果

dTBI2: A Calibrated, Tunable Device for Administering Traumatic Brain Injury in Drosophila.

dTBI2：一种经过校准、可调谐的设备，用于治疗果蝇脑外伤。

• DOI: 10.1002/cpz1.996
• 发表时间: 2024
• 期刊: Current protocols
• 作者: Ratner,StephenW;Fetchko,Michael;Mathivanan,AkankshaS;Kelly,SeannaE;Gupta,Shambhavi;Barber,AnnikaF
• 通讯作者: Barber,AnnikaF