Microglia in White Matter Repair after TBI

小胶质细胞在 TBI 后白质修复中的作用

• 批准号: 10436769
• 负责人: Dandan Sun
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436769
• 关键词: 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; Measurement; Mediating; Microglia; Military Personnel; Modeling; Motor; Mus; Myelin; Myelin Sheath; NADPH Oxidase; Nervous System Physiology; Neurocognitive; Neuroglia; Neurologic; Neurons; Oligodendroglia; Patients; Phagocytes; Phagocytosis; Pharmacology; Phenotype; Pilot Projects; Play; Population; Production; Protein Isoforms; Proteins; Recovery of Function; Regulation; Reporting; Role; Sensorimotor functions; Stains; Stroke; Structure; Superoxides; Synapses; 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; macrophage; mild traumatic brain injury; military service; myelination; oligodendrocyte progenitor; preservation; remyelination; repaired; response; service member; spatiotemporal; stem cell survival; stroke model; therapeutic target; tissue repair; transcriptome; transcriptome sequencing; uptake; white matter; white matter injury

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.

创伤性脑损伤 (TBI) 每年影响超过 250 万人（美国平民和退伍军人），占 占所有伤害相关死亡人数的 30%。 TBI 患者经常出现长期的创伤性轴突损伤、髓鞘质丧失 鞘，并抑制少突胶质细胞的成熟，这有助于运动、认知、行为和 精神缺陷。然而，TBI 引起的白质损伤和脑损伤的潜在机制 轴突髓鞘再生仍然知之甚少。小胶质细胞激活在白质损伤和组织中发挥作用 维修。小胶质细胞/巨噬细胞促炎性和适应性表型之间转换的调节是 对于少突胶质细胞分化、髓鞘再生以及突触重塑很重要。我们最近 发现 Na/H 交换异构体 1 (NHE1) 蛋白介导的 H+ 流出维持小胶质细胞胞内 pH (pHi) 稳态促进 NADPH 氧化酶介导的自由基超氧化物产生和细胞因子 分泌。我们报道了 Cx3cr1-CreER;Nheflox/flox (Nhe1 KO) 小鼠中小胶质细胞 Nhe1 的选择性缺失 在实验性局部缺血中保留少突胶质细胞并改善感觉运动功能恢复 中风模型，可能是由小胶质细胞-少突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。我们使用受控皮质冲击 (CCI) 诱导的 TBI 模型进行的初步研究还表明，Nhe1 KO 小鼠表现出促炎反应降低和 APC+ 成熟少突胶质细胞计数增加 创伤性脑损伤。特别是，TBI 后施用 NHE1 蛋白抑制剂 HOE642 可加速神经功能 中风或创伤性脑损伤后小鼠的恢复。这些研究确定 NHE1 蛋白是一种潜在的治疗方法 调节 TBI 后髓鞘再生和组织修复中小胶质细胞介导的炎症的靶点。在这个 根据建议，我们将测试一个中心假设：1）小胶质细胞 NHE1 蛋白的激活刺激 促炎症反应，随后导致少突胶质细胞死亡和脱髓鞘； 2） 选择性删除小胶质细胞 NHE1 蛋白可促进增殖、分化和存活 少突胶质细胞； 3）抑制NHE1蛋白活性还可以刺激小胶质细胞的吞噬功能 清除髓鞘碎片，促进 TBI 后神经元突触的修剪和重塑。完成 该项目将使我们能够获得有关白色小胶质细胞-少突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 小鼠系和 TBI后对NHE1功能的药理学抑制将揭示靶向NHE1蛋白的治疗潜力 用于减少脑外伤后白质损伤并改善组织修复。