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; 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.

项目摘要/摘要 每年，近200万人在美国承受创伤性脑损伤（TBI）。 TBI是所有与伤害有关的死亡的三分之一的因素，超过40％ 幸存者遭受长期障碍，包括睡眠和昼夜节律疾病 （SCRD）。这些疾病可能是代谢的终生风险升高或加剧寿命升高的基础 TBI患者发现的疾病，情绪障碍和神经退行性疾病。而 TBI患者长期以来已经认识到SCRD的患病率并在动物中概括 模型，在分子和电路水平上这些疾病的基础机制是 未知。该提案利用果蝇的Melanogaster遗传模型来识别 有助于TBI引起的SCR的基因并确定睡眠在 TBI的介导分子和生理结果。根据已发布和 初步数据，我们假设TBI诱导的炎症反应破坏了昼夜节律 和大脑中的睡眠调节系统，形成延长的正反馈回路 炎。我们已经建立了一个可调的，特异性的果蝇TBI范式 导致慢性睡眠减少和减少运动的昼夜节律行为行为的节奏 受伤。在此模型中，轻度损伤会导致SCRD而不会影响死亡率。我们寻求回答 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之后的各个阶段？ （AIM 2）可以针对睡眠和昼夜节律的干预措施 受伤后改善了TBI的结果？在AIM 1中，我们将进行候选击倒/淘汰赛 促炎基因的筛选，以鉴定有助于睡眠方面的基因 受伤后的昼夜节律中断。在AIM 2中，我们将对 TBI两性苍蝇的TBI之后发生了变化。我们将使用这些数据设计 TBI之后的各个阶段的睡眠操纵范式检查睡眠如何变化 TBI影响寿命，运动功能以及神经元和神经胶质健康。追求这些目标，我 将结合生理表征和睡眠操纵的遗传工具以及 飞行模型中可用的行为测定。新型果蝇TBI模型的使用将允许 无与伦比的时间和空间控制的遗传操作，不仅识别 基因在SCRD中很重要，但是它们在什么组织中起作用。拟议的研究将是 有影响力，因为它将定义将基本大脑过程与TBI和TBI和 为未来的调查提供了基础，具有转化的影响。