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.

项目概要 每年有 18,000 名美国人遭受脊髓损伤 (SCI) 的困扰，并对身体功能和健康造成毁灭性影响 心理健康。最初的脊髓损伤会引起一系列延迟性损伤（“继发性损伤”） 通过有害的炎症反应。这种延迟损害是紧急干预的窗口，但目前还没有 有效的神经保护性 SCI 治疗。免疫激活广泛受到昼夜节律系统的调节， 优化全天的生理活动。重要的是，关键的昼夜节律因子充当转录调节因子 它们控制生物钟，同时也控制体内的关键过程，例如免疫反应。那里 迫切需要阐明治疗 SCI 的新方法，例如调节昼夜节律神经免疫 轴，可以改善解剖和行为缺陷。一种有前途的昼夜节律蛋白 REV-ERB 是一种 抑制先天免疫细胞（包括中枢神经系统细胞）反应性的转录抑制因子 克罗胶质细胞和外周巨噬细胞。该提案的总体目标是确定 REV-ERB 是否 一种昼夜节律神经免疫抑制剂，可靶向改善神经保护和神经功能 SCI之后。过去的研究表明，SCI 扰乱了中心昼夜节律，这可能会导致过度炎症 化。初步数据显示，激活 REV-ERB 可降低巨噬细胞反应性并增强运动能力 SCI后恢复。因此，该建议很重要，因为确定新的保护目标将有助于改善 SCI 后的继发性损伤和缺陷。该提案的中心假设是放大 REV-ERB 激活 可以改善 SCI 后的神经保护、运动功能、疼痛缓解和情绪。理由是重新 SCI 后通过增强 REV-ERB 来压制有害的炎症转录程序将导致神经损伤 保护，这将对 SCI 治疗产生影响。该提案解决了这些具体目标：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 SCI后； 2) 确定中枢神经系统巨噬细胞靶向的 REV-ERB 过表达是否可以改善组织保护 以及 SCI 后的神经系统恢复； 3) 确定 REV-ERB 激活的药理作用是否有益于- 炎症细胞状态，促进神经保护和 SCI 恢复。该提案首次将现场结合起来 特定的 SCI 和昼夜节律神经免疫方法，包括震中的解剖和分子分析； 运动、疼痛和情绪相关的行为；细胞培养；以及尖端的单细胞 RNA 测序。因此， 拟议的研究具有创新性，因为它将 SCI、昼夜节律和 神经炎症。这一贡献将是意义重大的：它将揭示优化的广泛的、临床相关的作用 神经免疫反应性，以改善神经保护，并促进运动恢复、缓解疼痛和 心理健康——脊髓损伤后。最终，这些知识可以为新颖的开发和实施提供信息 改善 SCI 患者康复和生活质量的疗法。