Microglia in White Matter Repair after TBI

小胶质细胞在 TBI 后白质修复中的作用

基本信息

批准号：
10553623
负责人：
Dandan Sun
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553623
关键词：
Acceleration Affect Axon Behavioral Black race Brain Cells Cessation of life Cognitive Cre-LoxP Data Demyelinations Dendritic Spines Exhibits Flow Cytometry Fluorescence Free Radicals Gold Homeostasis Impairment Inflammation Inflammatory Inflammatory Response Injury Ischemic Stroke Knock-out Knockout Mice Knowledge Latex Bead LoxP-flanked allele Macrophage Measurement Mediating Microglia Military Personnel Modeling Motor Mus Myelin Myelin Sheath NADPH Oxidase Nervous System Physiology Neurocognitive Neuroglia Neurologic Neurons Oligodendroglia Phagocytes Phagocytosis Phenotype Pilot Projects Population Production Proliferating Protein Isoforms Proteins Recovery of Function Regulation Reporting Role Sensorimotor functions Stains Stroke Structure Superoxides Synapses TBI Patients Testing Therapeutic Transmission Electron Microscopy Traumatic Brain Injury Traumatic Brain Injury recovery Veterans Western Blotting Wild Type Mouse axon injury controlled cortical impact cytokine density experience improved inhibitor injury and repair mild traumatic brain injury military service myelination oligodendrocyte progenitor pharmacologic preservation remyelination repaired service member spatiotemporal stem cells stroke model therapeutic target tissue repair transcriptome transcriptome sequencing uptake white matter white matter injury

项目摘要

Traumatic brain injury (TBI) affects more than 2.5 million (US civilian and veterans) annually and accounts for 30% of all injury-related fatalities. TBI patients often develop long-lasting traumatic axonal injury, loss of myelin sheath, and inhibition of oligodendrocyte maturation, which contribute to motor, cognitive, behavioral, and psychiatric deficits. However, the underlying mechanisms of TBI-induced white matter injury and impairment of axonal remyelination remain poorly understood. Microglia activation plays a role in white matter injury and tissue repair. Regulation of a switch between pro-inflammatory and adaptive phenotypes of microglia/macrophage is important for oligodendrocyte differentiation, remyelination, as well as remodeling of synapses. We recently discovered that Na/H exchanger isoform 1 (NHE1) protein-mediated H+ efflux maintains microglial intracellular pH (pHi) homeostasis to promote NADPH oxidase-mediated free radical superoxide production and cytokine secretion. We reported that selective deletion of microglial Nhe1 in the Cx3cr1-CreER;Nheflox/flox (Nhe1 KO) mice preserved oligodendrocytes and improved sensorimotor function recovery in an experimental focal ischemic stroke model, which may result from microglia-oligodendrocyte interactions and microglia-mediated synapse plasticity. Our pilot study using a controlled cortical impact (CCI)-induced TBI model also reveals that Nhe1 KO mice exhibited decreased pro-inflammatory responses and increased APC+ mature oligodendrocyte counts after TBI. Especially, post-TBI administration of the NHE1 protein inhibitor HOE642 accelerated neurological function recovery in mice after either stroke or TBI. These studies identified NHE1 protein as a potential therapeutic target for modulating microglia-mediated inflammation in remyelination and tissue repair after TBI. In this proposal, we will test a central hypothesis that: 1) activation of microglial NHE1 protein stimulates proinflammatory responses and subsequently contributes to oligodendrocyte death and demyelination; 2) selective deletion of microglial NHE1 protein promotes proliferation, differentiation, and survival of oligodendrocytes; 3) inhibition of NHE1 protein activity also stimulates microglial phagocytic function for clearance of myelin debris, which facilitates neuronal synapse pruning and remodeling after TBI. Completion of this project will enable us to gain new knowledge about the roles of microglia-oligodendrocyte interactions in white matter injury and tissue repair after TBI. The combined approaches with the microglial Cre-LoxP mouse line and post-TBI pharmacological inhibition of NHE1 function will reveal therapeutic potentials of targeting NHE1 protein for reducing white matter injury and improving tissue repair after TBI.

脑外伤（TBI）每年影响超过250万（美国的平民和退伍军人），并说明所有与伤害有关的死亡人数中有30％。 TBI患者经常会出现持久的创伤性轴突损伤，髓磷脂的丧失鞘和抑制少突胶质细胞的成熟，这有助于运动，认知，行为和精神病缺陷。但是，TBI引起的白质损伤的基本机制和损害轴突透明度仍然了解不足。小胶质细胞激活在白质损伤和组织中起作用维修。调节小胶质细胞/巨噬细胞的促炎和适应性表型之间的切换是对于少突胶质细胞分化，再生以及突触的重塑至关重要。我们最近发现Na/H交换器同工型1（NHE1）蛋白介导的H+外排保持小胶质细胞内细胞内 pH（PHI）稳态促进NADPH氧化酶介导的自由基超氧化物的产生和细胞因子分泌。我们报道了CX3CR1-CREER中的小胶质细胞NHE1的选择性删除； NHEFLOX/FLOX（NHE1 KO）小鼠在实验局灶性缺血中，保留的少突胶质细胞和改善的感觉运动功能恢复中风模型，这可能是由小胶质细胞 - 寡胶质细胞相互作用和小胶质细胞介导的突触引起的可塑性。我们使用受控皮质影响（CCI）诱导的TBI模型的试点研究也表明NHE1 KO 小鼠表现出降低的促炎反应，并增加了APC+成熟的少突胶质细胞计数 TBI。特别是，TBI后NHE1蛋白抑制剂HOE642加速神经功能中风或TBI后小鼠的恢复。这些研究将NHE1蛋白确定为潜在的治疗性在TBI后调节小胶质细胞介导的雷恩和组织修复中的炎症的靶标。在这个提案，我们将检验一个中心假设：1）小胶质细胞NHE1蛋白的激活刺激促炎反应，随后导致少突胶质细胞死亡和脱髓鞘； 2）小胶质细胞NHE1蛋白的选择性缺失促进少突胶质细胞； 3）抑制NHE1蛋白活性还刺激了小胶质细胞功能髓磷脂碎片的清除，可促进TBI后神经元突触修剪和重塑。完成该项目将使我们能够获得有关白色小胶质细胞相互作用的作用的新知识 TBI后物质损伤和组织修复。与小胶质细胞cre-loxp小鼠系的组合方法和 TBI药理学对NHE1功能的抑制作用将揭示靶向NHE1蛋白的治疗潜力用于减少白质损伤并改善TBI后的组织修复。