Brain-invading monocytes promote the deleterious consequences of status epilepticus

侵入大脑的单核细胞会促进癫痫持续状态的有害后果

基本信息

  • 批准号:
    10062530
  • 负责人:
  • 金额:
    $ 34.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Status epilepticus (SE) is a frequent neurological emergency that can reduce the quality of life of those affected, produce cognitive deficits, and result in the development of epilepsy. Brain inflammation is an invariable feature of seizure activity and is believed to contribute to neuronal demise and exacerbate the deleterious behavioral consequences of unabated seizures. However, the involvement of blood-borne immune cells in the brain's inflammatory reaction after seizures remains unresolved. We have recently identified a subclass of circulating monocytes that invades brain tissue after seizures. Our findings indicate that blocking monocyte infiltration, via Ccr2 knockout, reduces the deleterious consequences of SE. These results prompt us to ask whether brain-invading monocytes are a novel therapeutic target to attenuate the adverse effects of seizures, alleviate cognitive dysfunction, and inhibit the development of epilepsy after SE. My hypothesis is that microglia-driven recruitment of brain-invading monocytes is a strong driver of SE-induced neurobehavioral deficits and epileptogenesis in the weeks following SE because pro-inflammatory monocytes migrate across the BBB promoting albumin extravasation into the brain. The lessons gleaned from completion of the proposed studies will lead to insights into myeloid cell biology in epilepsy as well as brain disease in general. The proposed studies will determine how the peripheral immune system can impact central immune reactions and contribute to co-morbidities, leading to decreased quality of life in individuals afflicted with epilepsy. Utilizing multiple techniques, my specific aims are designed to investigate and validate important components of this hypothesis. Aim 1. To test the hypothesis that brain-infiltrating monocytes engraft in the brain and maintain their own pro-inflammatory profile, exacerbating a pro-inflammatory response in microglia. Aim 2. To test the hypothesis that albumin extravasation is reliant on monocyte migration across the BBB. Aim 3. To determine if blocking monocyte brain entry exerts antiepileptogenic or disease modifying effects after SE. If our aims are achieved, then this would support continued efforts for targeting peripheral monocytes with therapies, which could have a significant impact on reducing the burden of neurological disease, a major mission of NINDS.
项目概要/摘要 癫痫持续状态 (SE) 是一种常见的神经急症,会降低患者的生活质量 受影响,产生认知缺陷,并导致癫痫的发展。脑部炎症是 癫痫发作活动的不变特征,被认为会导致神经元死亡并加剧 癫痫发作有增无减的有害行为后果。然而,血源性免疫的参与 癫痫发作后大脑细胞的炎症反应仍未解决。我们最近确定了一个 癫痫发作后侵入脑组织的循环单核细胞亚类。我们的研究结果表明,阻塞 通过 Ccr2 敲除实现单核细胞浸润,可减少 SE 的有害后果。这些结果提示我们 询问侵入大脑的单核细胞是否是减轻副作用的新治疗靶点 癫痫发作,缓解认知功能障碍,并抑制 SE 后癫痫的发展。 我的假设是,小胶质细胞驱动的大脑侵入单核细胞的募集是 SE 诱导的强烈驱动因素 SE 后数周内神经行为缺陷和癫痫发生,因为促炎性单核细胞 穿过血脑屏障促进白蛋白外渗到大脑中。从完成中吸取的教训 拟议的研究将有助于深入了解癫痫和脑疾病中的骨髓细胞生物学 一般的。拟议的研究将确定外周免疫系统如何影响中枢免疫 反应并导致合并症,导致患者的生活质量下降 癫痫。利用多种技术,我的具体目标是调查和验证重要的 这个假设的组成部分。 目标 1. 检验脑浸润单核细胞植入大脑并维持其功能的假设 自身的促炎特征,加剧小胶质细胞的促炎反应。 目标 2. 检验白蛋白外渗依赖于单核细胞跨膜迁移的假设 BBB。 目标 3. 确定阻断单核细胞进入大脑是否具有抗癫痫或改善疾病的作用 SE后的效果。 如果我们的目标实现,那么这将支持继续努力靶向外周单核细胞 疗法,这可能对减轻神经系统疾病的负担产生重大影响,神经系统疾病是一个主要的疾病 NINDS 的使命。

项目成果

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Nicholas Varvel其他文献

Nicholas Varvel的其他文献

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{{ truncateString('Nicholas Varvel', 18)}}的其他基金

Brain-invading monocytes promote the deleterious consequences of status epilepticus
侵入大脑的单核细胞会促进癫痫持续状态的有害后果
  • 批准号:
    10303046
  • 财政年份:
    2019
  • 资助金额:
    $ 34.13万
  • 项目类别:
Brain-invading monocytes promote the deleterious consequences of status epilepticus
侵入大脑的单核细胞会促进癫痫持续状态的有害后果
  • 批准号:
    9913177
  • 财政年份:
    2019
  • 资助金额:
    $ 34.13万
  • 项目类别:

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