Circadian control of neuroinflammation after spinal cord injury

脊髓损伤后神经炎症的昼夜节律控制

• 批准号: 10639178
• 负责人: Andrew Gaudet
• 金额: $ 44.47万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639178
• 关键词: Acute; Address; Agonist; American; Anatomy; Anti-Inflammatory Agents; Behavior; Behavioral; Blood; Cell Culture Techniques; Cells; Central Nervous System; Circadian Dysregulation; Circadian Rhythms; Coculture Techniques; Data; Development; Genes; Genetic Transcription; Health; Hospitals; Immune; Immune system; Inflammation; Inflammatory; Inflammatory Response; Injections; Intervention; Knockout Mice; Knowledge; Lesion; Link; Locomotion; Locomotor Recovery; Macrophage; Mental Health; Methods; Microglia; Mission; Molecular Analysis; Moods; Motor; Mus; Nervous System Physiology; Neuroimmune; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neurological outcome; Neuronal Plasticity; Neurons; Pain; Pathway interactions; Peripheral; Physiological; Process; Proteins; Public Health; Quality of life; Recovery; Recovery of Function; Repression; Research; Role; Severities; Spinal cord injury; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Transcription Repressor; Transgenic Organisms; United States National Institutes of Health; behavior test; circadian; circadian pacemaker; clinical predictors; clinically relevant; disability; immune activation; improved; injury recovery; innovation; neuroimmunology; neuroinflammation; neurological recovery; neuroprotection; neurotoxic; novel strategies; novel therapeutics; overexpression; pain relief; pain symptom; pharmacologic; pre-clinical; programs; repaired; single-cell RNA sequencing; tissue repair; transcriptomics

PROJECT SUMMARY Spinal cord injury (SCI) newly afflicts 18,000 Americans/year and has devastating effects on body function and mental health. Initial spinal cord trauma elicits a delayed cascade of damage (“secondary damage”) that is driven by a harmful inflammatory response. This delayed damage is a window for acute intervention, yet there are no effective neuroprotective SCI therapies. Immune activation is broadly regulated by the circadian system, which optimizes across-day physiologic activities. Importantly, pivotal circadian factors act as transcriptional regulators that govern the circadian clock – but also control crucial processes in the body, such as immune reactivity. There is a critical need to illuminate novel approaches for treating SCI, such as modulating the circadian-neuroimmune axis, that could ameliorate anatomical and behavioral deficits. One promising circadian protein, REV-ERB, is a transcriptional repressor that dampens reactivity of innate immune cells, including central nervous system mi- croglia and peripheral macrophages. The overall objective of this proposal is to establish whether REV-ERB is a circadian-neuroimmune repressor that can be targeted to improve neuroprotection and neurologic function after SCI. Past studies show that SCI perturbs epicenter circadian rhythms, which likely enables excess inflam- mation. Preliminary data reveal that activating REV-ERB reduces macrophage reactivity and boosts locomotor recovery after SCI. Therefore, this proposal is important, as identifying new protective targets will help ameliorate secondary damage and deficits after SCI. This proposal’s central hypothesis is that amplifying REV-ERB activa- tion will improve neuroprotection, locomotor function, pain relief, and mood after SCI. The rationale is that re- pressing harmful inflammatory transcriptional programs after SCI by boosting REV-ERBs will lead to neuropro- tection, which would have implications for SCI therapies. This proposal addresses these Specific Aims: 1) Reveal whether microglial and/or macrophage REV-ERBs are required to limit neurotoxic and neurologic detriments after SCI; 2) Establish whether CNS macrophage-targeted REV-ERB overexpression improves tissue sparing and neurologic recovery after SCI; and 3) Determine whether pharmacologic REV-ERB activation benefits in- flammatory cell state to boost neuroprotection and SCI recovery. For the first time, this proposal combines field- specific SCI and circadian-neuroimmune methods, including anatomical and molecular analysis of epicenter; motor, pain, and mood-related behaviors; cell culture; and cutting-edge single-cell RNA-sequencing. Thus, the proposed research is innovative, as it links unique ideas, expertise, and methods in SCI, circadian rhythms, and neuroinflammation. This contribution will be significant: it will reveal the broad, clinically relevant role of optimizing neuroimmune reactivity for improving neuroprotection – and for promoting locomotor recovery, pain relief, and mental health – after SCI. Ultimately, this knowledge could inform development and implementation of novel therapies for improving recovery and quality of life for those with SCI.

项目摘要 脊髓损伤（SCI）新近折磨18,000名美国人/年，对身体功能和 心理健康。最初的脊髓创伤引起了延迟的损伤级联（“次要伤害”） 通过有害的炎症反应。这种延迟的伤害是急性干预的窗口，但没有 有效的神经保护性科学疗法。免疫激活受到昼夜节律的广泛调节，该系统 优化整日生理活动。重要的是，关键昼夜节律因素充当转录调节因子 控制昼夜节律的时钟 - 但也控制体内的关键过程，例如免疫反应性。那里 是阐明治疗SCI的新颖方法的迫切需要，例如调节昼夜节律 - 神经免疫性 轴，可以改善解剖学和行为缺陷。一种有前途的昼夜节律蛋白Rev-erb是 转录复制品，该死的先天性免疫电池的反应性，包括中枢神经系统 Croglia和外围巨噬细胞。该提议的总体目的是确定Rev-erb是否是 可以针对改善神经保护和神经系统功能的昼夜节律神经免疫性复制品 科幻之后。过去的研究表明，Sci震撼了中心的昼夜节律，这可能超过了Inderm- mation。初步数据表明，激活Rev-ERB降低了巨噬细胞的反应性，并提高了运动 科学后的恢复。因此，该建议很重要，因为识别新的受保护目标将有助于改善 次要损坏并在SCI后定义。该提议的中心假设是放大Rev-erb Activa- SCI后将改善神经保护作用，运动功能，缓解疼痛和情绪。理由是 通过促进REV-ERBS在SCI之后施压有害的炎症转录程序将导致神经 Tection，这将对SCI疗法产生影响。该提案解决了以下具体目的：1）揭示 是否需要小胶质细胞和/或巨噬细胞Rev-ERB来限制神经毒性和神经系统损害 科幻之后； 2）确定CNS巨噬细胞靶向的Rev-ERB是否可以改善组织的保留 科学后的神经系统恢复； 3）确定药物结肠化Rev-erb激活是否有益于 燃料细胞状态以促进神经保护和SCI恢复。该提议首次结合了现场 - 特定的SCI和昼夜节律免疫方法，包括震中的解剖学和分子分析； 运动，疼痛和与情绪相关的行为；细胞培养；和尖端的单细胞RNA测序。那， 拟议的研究具有创新性，因为它链接了SCI，昼夜节律的独特思想，专业知识和方法 神经炎症。这项贡献将是重要的：它将揭示优化的广泛，临床相关的作用 神经免疫性反应性改善神经保护作用 - 以及促进运动恢复，缓解疼痛和 心理健康 - 科幻之后。最终，这些知识可以为新颖的发展和实施提供信息 改善SCI患者的恢复和生活质量的疗法。