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: 10044411
• 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/10044411
• 关键词: Affect; Axon; Behavioral; Brain; Cells; Cessation of life; Cognitive; Cre-LoxP; Data; Demyelinations; Dendritic Spines; Exhibits; Flow Cytometry; Fluorescence; Free Radicals; Gold; Homeostasis; Immunoblotting; 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; Wild Type Mouse; axon injury; controlled cortical impact; cytokine; density; experience; improved; inhibitor/antagonist; 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），并占美国人口的10%