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:
    10044411
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 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 2023-12-31
  • 项目状态:
    已结题

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), 占所有与伤害有关的死亡人数的30%。TBI患者通常会出现长期的创伤性轴索损伤,髓鞘丢失, 鞘,并抑制少突胶质细胞成熟,这有助于运动,认知,行为, 精神缺陷然而,TBI诱导的白色物质损伤和脑损伤的潜在机制尚不清楚。 轴突髓鞘再生仍然知之甚少。小胶质细胞活化在白色物质损伤和组织损伤中发挥作用 修复.调节小胶质细胞/巨噬细胞的促炎和适应性表型之间的转换是 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(NHE 1)蛋白介导的H+流出维持小胶质细胞内 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 分泌物我们报道了在Cx 3cr 1-CreER;Nheflox/flox(Nhe 1 KO)小鼠中选择性缺失小胶质细胞Nhe 1, 在实验性局灶性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,其可能由小胶质细胞-少突胶质细胞相互作用和小胶质细胞介导突触引起 可塑性我们使用受控皮质撞击(CCI)诱导的TBI模型进行的初步研究也表明,Nhe 1 KO 小鼠表现出减少的促炎反应和增加的APC+成熟少突胶质细胞计数, 创伤性脑损伤特别是,TBI后给予NHE 1蛋白抑制剂HOE 642可加速神经功能 中风或TBI后小鼠的恢复。这些研究将NHE 1蛋白确定为潜在的治疗剂 靶向调节TBI后髓鞘再生和组织修复中小胶质细胞介导的炎症。在这 我们将测试一个中心假设,即:1)小胶质细胞NHE 1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) 选择性缺失小胶质细胞NHE 1蛋白促进了细胞的增殖、分化和存活。 3)抑制NHE 1蛋白活性也刺激小胶质细胞吞噬功能, 髓鞘碎片的清除,这有助于TBI后神经元突触的修剪和重塑。完成 这个项目将使我们能够获得关于小胶质细胞-少突胶质细胞相互作用在白色中的作用的新知识。 TBI后的物质损伤和组织修复。使用小胶质细胞Cre-LoxP小鼠系和 TBI后NHE 1功能的药理学抑制将揭示靶向NHE 1蛋白的治疗潜力 用于减少TBI后的白色物质损伤和改善组织修复。

项目成果

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Dandan Sun其他文献

Dandan Sun的其他文献

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{{ truncateString('Dandan Sun', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10373039
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10231728
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10618190
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
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:
    9778141
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
ShEEP Request for a High-Content Screening (HCS) Platform
ShEEP 请求建立高内涵筛选 (HCS) 平台
  • 批准号:
    10175276
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
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:
    10553623
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Long Non-Coding RNAs and Cerebral Angiogenesis in Ischemic Stroke
长非编码 RNA 与缺血性中风中的脑血管生成
  • 批准号:
    10605296
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Regulatory T cell as a restorative therapy for ischemic stroke
调节性 T 细胞作为缺血性中风的恢复疗法
  • 批准号:
    10261318
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Regulatory T cell as a restorative therapy for ischemic stroke
调节性 T 细胞作为缺血性中风的恢复疗法
  • 批准号:
    9619010
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:

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