Targeting Microglia in Febrile Status Epilepticus

针对小胶质细胞治疗发热性癫痫持续状态

• 批准号: 10297475
• 负责人: Ukpong Bassey Eyo
• 金额: $ 47.07万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297475
• 关键词: Address; Adult; Affect; Age; Anti-Inflammatory Agents; Astrocytes; Behavioral; Body Temperature; Brain; Cells; Chemicals; Child; Childhood; Complex; Conflict (Psychology); Convulsions; Data; Development; Disease; Environment; Epilepsy; Exposure to; Febrile Convulsions; Fever; G-Protein-Coupled Receptors; Genetic; Histopathology; Homeostasis; Hyperactivity; Immune; Immunocompetent; Induced Hyperthermia; Inflammation; Inflammation Mediators; Life; Literature; Masks; Microglia; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neuroimmune; Neuronal Dysfunction; Neurons; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenocopy; Phenotype; Play; Pre-Clinical Model; Purines; Research; Research Personnel; Risk Factors; Rodent Model; Role; Seizures; Severities; Status Epilepticus; Temporal Lobe Epilepsy; Testing; Work; brain cell; cell type; cytokine; drug development; early life exposure; experience; interest; mortality; mouse model; neuroinflammation; novel; novel strategies; receptor; receptor function; selective expression

PROJECT SUMMARY Febrile seizures are the most common form of childhood seizures. They affect 2-5% of children between the ages of 6 and 60 months. They occur with a rise in body temperature that is often associated with a fever, though the underlying mechanisms are not fully understood. In a subset of children with febrile seizure, seizures and convulsions are prolonged and are referred to as febrile status epilepticus (fSE). Some children that experience fSE go on to develop epilepsy in childhood or adulthood making childhood fSE a risk factor for subsequently developing epilepsy. Although the underlying mechanisms governing status epilepticus and epilepsy are known to emanate from neuronal dysfunction, compelling research in recent years suggest contributions from inflammation, broadly characterized, in fSE. This is evidenced by increased inflammatory mediators in fSE and reduced SE with broad-acting anti-inflammatory drugs. However, inflammation, can be generated by resident cells of the brain such as microglia and astrocytes as well as peripheral immune cells that can release inflammatory mediators outside the brain to alter neuronal function. Current research has thus far failed to delineate cell-specific contributions to inflammation in the context of fSE. In this project, we have begun to determine distinct contributions from microglia, the primary resident immune cell of the brain, in fSE. Given broadly detrimental roles for inflammation in fSE, it has been assumed that microglia, as inflammation-competent cells, promote fSE. Contrary to this assumption, our preliminary experimental results in both chemical- and hyperthermia- induced SE, indicate that microglia actually play beneficial roles in reducing SE severity in mouse models. Moreover, we have identified the microglial-specific P2Y12R as a candidate regulator of microglial beneficial contributions during experimental SE. Therefore, using well-established microglial elimination approaches, we will now: (1) test for general microglial roles in hyperthermia-induced SE and determine whether microglial regulate the neuroinflammatory environment in SE (Aim 1); (2) test for specific microglial P2Y12R roles in regulating microglial beneficial contributions to controlling hyperthermia-induced SE (Aim 2); and (3) determine microglial P2Y12R roles in the progression to temporal lobe epilepsy (TLE) using a novel mouse model follow early life exposure to hyperthermia-induced SE (Aim 3). This project is a first to adequately clarify microglial contributions in a mouse model of fSE as a pre-clinical model. This work will provide a framework for targeting microglia as a novel approach to ameliorate SE in general and fSE in particular.

项目概要 高热惊厥是儿童惊厥最常见的形式。它们影响 2-5% 的儿童 年龄在 6 至 60 个月之间。它们随着体温升高而发生，通常是 与发烧有关，但其潜在机制尚不完全清楚。在一个子集中 小儿热性惊厥，惊厥、抽搐持续时间较长，称为热性惊厥。 癫痫持续状态（fSE）。一些经历过 fSE 的儿童会在童年或 成年期使儿童 fSE 成为随后发生癫痫的危险因素。虽然 已知控制癫痫持续状态和癫痫的潜在机制源自 近年来令人信服的研究表明，神经元功能障碍是由炎症、 在 fSE 中具有广泛的特征。 fSE 中炎症介质的增加证明了这一点 使用广效抗炎药减少 SE。然而，炎症可通过以下方式产生： 大脑的常驻细胞，例如小胶质细胞和星形胶质细胞以及外周免疫细胞 可以在大脑外释放炎症介质以改变神经元功能。目前的研究有 迄今为止，未能在 fSE 的背景下描述细胞特异性对炎症的影响。在这个 项目中，我们已经开始确定小胶质细胞（主要居民）的独特贡献 大脑的免疫细胞，在 fSE 中。鉴于炎症在 fSE 中具有广泛的有害作用， 假设小胶质细胞作为炎症活性细胞，促进 fSE。与这个假设相反， 我们在化学和热疗诱导 SE 中的初步实验结果表明 在小鼠模型中，小胶质细胞实际上在降低 SE 严重程度方面发挥着有益的作用。此外，我们还有 确定小胶质细胞特异性 P2Y12R 作为小胶质细胞有益贡献的候选调节因子 在实验SE期间。因此，使用成熟的小胶质细胞消除方法，我们将 现在：（1）测试小胶质细胞在热疗诱导的 SE 中的一般作用，并确定是否 小胶质细胞调节 SE 中的神经炎症环境（目标 1）； (2)特定小胶质细胞的测试 P2Y12R 在调节小胶质细胞对控制高热诱导 SE 的有益贡献中的作用 （目标 2）； (3) 确定小胶质细胞 P2Y12R 在颞叶癫痫进展中的作用 (TLE) 使用一种新型小鼠模型，追踪生命早期暴露于高温引起的 SE 的情况（目标 3）。这 该项目是第一个充分阐明小胶质细胞在 fSE 小鼠模型中作为临床前研究的贡献的项目 模型。这项工作将为靶向小胶质细胞提供一个框架，作为改善 一般而言 SE，特别是 fSE。