Brain-invading monocytes promote the deleterious consequences of status epilepticus

项目摘要/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，产生认知障碍，并导致癫痫的发展。脑部炎症是一种 癫痫发作活动的不变特征，被认为有助于神经元死亡和加剧 有增无减的癫痫发作的有害行为后果。然而，参与血液传播的免疫 癫痫发作后大脑中的炎症反应细胞仍未得到解决。我们最近发现了一种 癫痫发作后侵入脑组织的循环单核细胞亚类。我们的发现表明，阻止 单核细胞的渗透，通过CCR2基因敲除，减少了SE的有害后果。这些结果提示我们 问脑侵袭单核细胞是否是减轻脑血管紧张素转换酶不良反应的新治疗靶点 能减轻癫痫发作，减轻认知功能障碍，抑制癫痫的发展。 我的假设是，小胶质细胞驱动的脑侵袭性单核细胞募集是SE诱导的强大驱动因素 癫痫发作后几周的神经行为缺陷和癫痫发生，因为促炎单核细胞 跨血脑屏障迁移，促进白蛋白渗入大脑。从完成工作中学到的教训 将导致对癫痫和脑疾病的髓系细胞生物学的深入了解 将军。拟议中的研究将确定外周免疫系统如何影响中枢免疫 反应，并导致共病，导致患者的生活质量下降 癫痫。利用多种技术，我的特定目标旨在调查和验证重要的 这一假设的组成部分。 目的1.验证脑浸润性单核细胞植入脑内的假说，并维持其 自身的促炎特征，加剧了小胶质细胞的促炎反应。 目的2.验证白蛋白外渗依赖于单核细胞迁移的假说。 BBB。 目的3.确定阻断单核细胞脑内进入是否具有抗癫痫作用或疾病改善作用 SE后的影响。 如果我们的目标实现，那么这将支持继续努力以外周血单核细胞为靶点 治疗，这可能对减轻神经系统疾病的负担产生重大影响，这是一项主要的 NINDS的使命。

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.