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
• 负责人: Nicholas Varvel
• 金额: $ 34.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9913177
• 关键词: Address; Adverse effects; Affect; Albumins; Amygdaloid structure; Antiepileptogenic; Anxiety; Astrocytosis; Attenuated; Behavior; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Candidate Disease Gene; Cell physiology; Cells; Cellular biology; Clinical Trials; Cognitive deficits; Deterioration; Development; Disease; Electroencephalography; Encephalitis; Endothelium; Enterobacteria phage P1 Cre recombinase; Epilepsy; Epileptogenesis; Event; Extravasation; Fluorescein-5-isothiocyanate; Frequencies; Future; Gene Expression Profiling; Glean; Immune; Immune system; Impaired cognition; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interdisciplinary Study; Invaded; Knock-out; Label; Lead; Life; Mediating; Medical emergency; Memory; Microglia; Mission; Modeling; Molecular; Mus; Myeloid Cells; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurological emergencies; Neuronal Injury; Neurons; Outcome; Outcome Measure; Pathway interactions; Peripheral; Pharmacology; Phenotype; Pilocarpine; Process; Quality of life; Reaction; Residual state; Rodent; Role; Seizures; Serum Albumin; Status Epilepticus; Techniques; Testing; Weight; Work; attenuation; brain tissue; comorbidity; conditional knockout; design; field study; immunoreaction; in vivo; insight; kainate; man; migration; monocyte; nano-string; nervous system disorder; neurobehavioral; neuroinflammation; neuron loss; new therapeutic target; novel; object recognition; prevent; primary outcome; recruit; therapeutic target

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.

项目总结/摘要 癫痫持续状态（SE）是一种常见的神经系统急症，可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。脑炎症是一种 癫痫发作活动的不变特征，并被认为有助于神经元死亡和加剧 癫痫发作的有害行为后果然而，血液免疫的参与 癫痫发作后大脑炎症反应的细胞仍然没有解决。我们最近发现了一个 在癫痫发作后侵入脑组织的循环单核细胞的亚类。我们的研究结果表明， 通过Ccr 2敲除的单核细胞浸润减少了SE的有害后果。这些结果促使我们 询问脑侵入单核细胞是否是一种新的治疗靶点， 癫痫发作，缓解认知功能障碍，抑制SE后癫痫的发展。 我的假设是，小胶质细胞驱动的脑侵入单核细胞的募集是SE诱导的单核细胞凋亡的一个强有力的驱动因素。 神经行为缺陷和癫痫发生在SE后的几周内，因为促炎性单核细胞 迁移穿过BBB，促进白蛋白外渗到脑中。从完成中吸取的教训 拟议的研究将深入了解癫痫和脑部疾病的骨髓细胞生物学 将军拟议的研究将确定外周免疫系统如何影响中枢免疫， 反应，并有助于共病，导致生活质量下降的个人患有 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.为了验证脑浸润单核细胞在脑中移植并维持其功能的假设， 自身的促炎特征，加剧了小胶质细胞的促炎反应。 目标二。为了检验白蛋白外渗依赖于单核细胞迁移穿过 BBB. 目标3.确定阻断单核细胞脑内进入是否发挥抗癫痫或改善疾病的作用 SE后的效果 如果我们的目标得以实现，那么这将支持继续努力靶向外周单核细胞， 治疗，这可能对减轻神经系统疾病的负担产生重大影响，这是一个主要的 NINDS的使命。