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.

项目总结