Glial immune signaling in radiation-induced brain injury

放射诱发的脑损伤中的胶质细胞免疫信号传导

基本信息

  • 批准号:
    10267303
  • 负责人:
  • 金额:
    $ 42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT: Glial immune signaling in radiation-induced brain injury. Cranial radiation therapy (CRT) for the treatment of CNS cancers often leads to unintended and debilitating cognitive impairments. CRT also remains the standard of care to counter brain metastases for other invasive cancers. However, the molecular and cellular mechanisms underlying CRT-induced cognitive decline are multifaceted and have not been completely resolved. Our past findings show that whole-brain, acute CRT induces progressive neurodegenerative changes, including oxidative stress, reduced neurogenesis, and increased neuroinflammation. Microglia and astrocytes form complex glial networks in the CNS by pruning and maintaining thousands of synapses that are actively involved in cognition. Yet, we have shown that CRT-induced cognitive disruption coincides with astrocytic hypertrophy, elevated expression of astrogliosis genes, and persistent microglial activation in rodent models. Therefore, we hypothesize that detrimental glial signaling significantly contributes to cognitive deficits. The complement system is a potent mediator of the glial activation, but it also has a range of non- immune functions in the CNS, including synaptic pruning and clearance of apoptotic cells and cellular debris which is detrimental if dysregulated. Particularly, global elevation in the expression of complement C1q and C3 in the CNS has been reported in neurodegenerative conditions. Our findings indicate that acute, whole-brain CRT-mediated chronic microglial activation and reactive astrocytes, elevated co-expression of complement proteins (C1q, C3) and specific receptors (C5aR1, TLR4) coincided with cognitive impairments. Reactive gliosis has been shown to upregulate complement cascade proteins that are destructive to synapses and associated with neurodegeneration. We hypothesize that brain cancer therapy-induced aberrant activation in the glial complement cascade leads to cognitive deficits. Our hypothesis is supported by two key preliminary data sets targeting complement signaling at the upstream (C1q) and the downstream (C5a) activation branch points. First, exposure of conditional microglia-selective C1q (knockdown) mice to CRT did not exhibit impaired cognition and showed a lack of neuroinflammation as compared to irradiated WT mice. Second, treatment with an orally active, BBB permeable, C5a receptor (C5aR1) antagonist ameliorated acute CRT-induced cognitive deficits and alleviated microglial activation in the irradiated brain. Our hypothesis will be addressed using a clinically relevant, fractionated, focal cranial irradiation paradigm ± temozolomide, transgenic and glioma- bearing syngeneic mouse models, and pharmacologic approaches designed to test mechanisms and therapeutic interventions to restore cognitive function in the impaired animals.
摘要:放射诱发的脑损伤中的神经胶质免疫信号传导。 用于治疗中枢神经系统癌症的颅脑放射治疗 (CRT) 常常会导致意想不到的副作用 使人衰弱的认知障碍。 CRT 仍然是对抗大脑的护理标准 其他侵袭性癌症的转移。然而,分子和细胞机制 CRT 引起的认知能力下降是多方面的,并且尚未完全得到解决 解决了。我们过去的研究结果表明,全脑急性 CRT 会导致进行性 神经退行性变化,包括氧化应激、神经发生减少和神经发生增加 神经炎症。小胶质细胞和星形胶质细胞通过修剪在中枢神经系统中形成复杂的神经胶质网络 并维持数千个积极参与认知的突触。然而,我们有 研究表明,CRT 引起的认知障碍与星形胶质细胞肥大同时发生, 星形胶质细胞增生基因的表达以及啮齿动物模型中小胶质细胞的持续激活。所以, 我们假设有害的神经胶质信号传导显着导致认知缺陷。这 补体系统是神经胶质细胞激活的有效介质,但它也具有一系列非- 中枢神经系统的免疫功能,包括突触修剪和凋亡细胞的清除 如果失调的话,细胞碎片是有害的。特别是,表达式中的全局提升 据报道,在神经退行性疾病中,中枢神经系统中的补体 C1q 和 C3 会减少。我们的 研究结果表明,急性、全脑 CRT 介导的慢性小胶质细胞激活和反应性 星形胶质细胞,补体蛋白(C1q、C3)和特定受体的共表达升高 (C5aR1、TLR4)与认知障碍同时发生。反应性神经胶质增生已被证明 上调对突触具有破坏性并与相关的补体级联蛋白 神经变性。我们假设脑癌治疗引起的异常激活 神经胶质补体级联反应导致认知缺陷。我们的假设有两个关键的支持 针对上游 (C1q) 和下游补体信号传导的初步数据集 (C5a)激活分支点。首先,暴露条件性小胶质细胞选择性 C1q(敲低) 接受 CRT 治疗的小鼠没有表现出认知受损,并且没有表现出神经炎症 与受辐射的 WT 小鼠相比。其次,采用口服活性、BBB 可渗透的 C5a 治疗 受体(C5aR1)拮抗剂可改善急性 CRT 诱导的认知缺陷并缓解 受辐射大脑中的小胶质细胞激活。我们的假设将通过临床来解决 相关的、分次的、局灶性颅脑照射范式±替莫唑胺、转基因和神经胶质瘤- 具有同基因小鼠模型和旨在测试机制的药理学方法 以及恢复受损动物认知功能的治疗干预。

项目成果

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Munjal M Acharya其他文献

Munjal M Acharya的其他文献

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{{ truncateString('Munjal M Acharya', 18)}}的其他基金

Neurotrophic strategy to mitigate chemotherapy-related brain injury
减轻化疗相关脑损伤的神经营养策略
  • 批准号:
    10735146
  • 财政年份:
    2023
  • 资助金额:
    $ 42万
  • 项目类别:
Stem cell-derived exosomes to ameliorate chemobrain
干细胞衍生的外泌体改善化学脑
  • 批准号:
    10584374
  • 财政年份:
    2023
  • 资助金额:
    $ 42万
  • 项目类别:
Glial immune signaling in radiation-induced brain injury
放射诱发的脑损伤中的胶质细胞免疫信号传导
  • 批准号:
    10426324
  • 财政年份:
    2021
  • 资助金额:
    $ 42万
  • 项目类别:
Glial immune signaling in radiation-induced brain injury
放射诱发的脑损伤中的胶质细胞免疫信号传导
  • 批准号:
    10693817
  • 财政年份:
    2021
  • 资助金额:
    $ 42万
  • 项目类别:

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