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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.

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%