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.

项目总结/文摘

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