Circadian control of neuroinflammation after spinal cord injury

项目总结 脊髓损伤(SCI)每年新折磨18,000名美国人，对身体功能和 心理健康。最初的脊髓损伤会引起延迟级联损伤(“二次损伤”)，这种损伤是由 通过一种有害的炎症反应。这种延迟的损害是急性干预的窗口，但没有 有效的神经保护性脊髓损伤疗法。免疫激活广泛地受到昼夜节律系统的调节， 优化全天生理活动。重要的是，关键的昼夜节律因子起转录调节作用。 它们控制着生物钟，但也控制着人体内的关键过程，如免疫反应。那里 迫切需要阐明治疗脊髓损伤的新方法，例如调节昼夜节律神经免疫。 轴，这可以改善解剖学和行为缺陷。一种很有前途的昼夜节律蛋白REV-ERB是一种 转录抑制因子可抑制包括中枢神经系统在内的天然免疫细胞的反应性。 胶质细胞和外周巨噬细胞。这项提案的总体目标是确定REV-ERB是否 一种可靶向改善神经保护和神经功能的昼夜节律神经免疫抑制物 在SCI之后。过去的研究表明，脊髓损伤扰乱了震中的昼夜节律，这可能使过度的炎症- 信息传递。初步数据显示，激活REV-ERB可降低巨噬细胞的反应性并促进运动 脊髓损伤后的康复。因此，这项建议很重要，因为确定新的保护目标将有助于改善 脊髓损伤后的继发性损伤和缺陷。这一建议的中心假设是放大REV-ERB活性- TION可改善脊髓损伤后的神经保护、运动功能、疼痛缓解和情绪。其基本原理是重新- 通过增强REV-ERB来抑制脊髓损伤后有害的炎性转录程序将导致神经递质- 保护，这将对脊髓损伤治疗产生影响。该提案涉及以下具体目标：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损害 脊髓损伤后；2)确定CNS巨噬细胞靶向的REV-ERB过表达是否改善了组织的保存 和脊髓损伤后的神经功能恢复；以及3)确定药物激活REV-ERB是否在- 炎性细胞状态促进神经保护和脊髓损伤恢复。这项提案首次将领域-- 特殊的脊髓损伤和昼夜神经免疫方法，包括对震中的解剖和分子分析； 运动、疼痛和情绪相关行为；细胞培养；以及尖端单细胞RNA测序。因此， 建议的研究是创新的，因为它将脊髓损伤、昼夜节律和 神经炎。这一贡献将是重大的：它将揭示优化的广泛、临床相关的作用 神经免疫反应性，用于改善神经保护，促进运动恢复，缓解疼痛，以及 精神健康--在SCI之后。最终，这些知识可以为小说的发展和实施提供信息 改善脊髓损伤患者康复和生活质量的治疗方法。

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.