Investigating the role of NG2-glia in the development of epilepsy

研究 NG2-胶质细胞在癫痫发展中的作用

基本信息

批准号：
10393332
负责人：
Laura Ann Bell
金额：
$ 4.06万
依托单位：
UNIVERSITY OF UTAH
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 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393332
关键词：
Active Sites Acute Address Affect Antiepileptogenic Brain Brain Injuries CSPG4 gene Calcium Calcium Signaling Cells Centers for Disease Control and Prevention (U.S.)Central Nervous System Infections Central Nervous System Viral Diseases Chronic Cicatrix Classification Confocal Microscopy Development Disease Epilepsy Epileptogenesis Etiology Event Foundations Future Generations Genetic Transcription Goals Hippocampus (Brain)Homeostasis Human Image Immunohistochemistry Infection Inflammation Injury Intervention Lead Lesion Life Link Maintenance Maps Maus Elberfeld virus Methods Modeling Molecular Molecular Target Morphology Neuraxis Neuroglia Neurologic Neuronal Plasticity Neurons Patients Pharmacology Phase Physiology Play Process Purines Purinoceptor Reaction Recovery Recovery of Function Refractory Reporter Research Research Project Grants Resources Role Seizures Severities Signal Transduction Site Slice Structure TMEV Therapeutic Time Transgenic Mice Traumatic Brain Injury Traumatic injury Viral Virus Diseases Work acquired epilepsy career cell type cellular targeting central nervous system injury experimental study extracellular genetic approach high risk improved in vivo intercellular communication mouse model multiphoton imaging nervous system disorder neural network novel oligodendrocyte progenitor organizational structure prevent promoter protein expression response stem cells therapeutic target transcriptomics treatment strategy two-photon

项目摘要

Project Summary According to the CDC, there are more than 3 million people with active epilepsy in the US. It is estimated that up to 50% of all epilepsy cases are initiated by a neurological insult and are called acquired epilepsy. Brain infections and traumatic brain injury are two major examples of common brain injuries that can lead to the development of acquired epilepsy. Although there is diversity in the etiology and the severity of the disorder, understanding the cellular and molecular mechanisms by which seizures develop will aid in uncovering novel ways to prevent epilepsy following high-risk CNS injuries. Evidence has accumulated indicating that glial cells play an important role in the initiation and maintenance of the prolonged neuroplasticity changes underlying the development of epilepsy. NG2-glia are commonly known as oligodendrocyte progenitor cells (OPCs). However, a growing body of evidence has led to their classification as a major glial cell-type in their own right. Recent evidence suggests that these cells play important roles in maintaining environmental homeostasis, and disruptions to NG2-glia function have now been highly implicated in the development and progression of neurologic disease. To investigate whether NG2-glia are involved in epilepsy development, in Aim 1, NG2-glia morphology, structural organization, and protein expression were evaluated in a viral infection-induced mouse model of acquired epilepsy. The analysis identified that NG2-glia have highly reactive morphology, increased proliferation, and are involved in scar formation both during viral infection and following viral clearance. These NG2-glia responses are also highly localized to the hippocampus, the site of active infection and the origin site of seizures. This is significant because, while likely triggered by the initiating infection, the NG2-glia reaction may continue to play an important role in long-term neuroplasticity deficits that lead to epilepsy. Preliminary experiments in Aim 2 demonstrate that extracellular purines (damage signals that are heavily produced in the hippocampus following viral infection) induce robust elevations in intracellular calcium in NG2- glia. This finding is important because calcium can be used as a functional readout to better understand the real- time dynamics and the environmental signals initiating the NG2-glia reaction to injury and infection. Future work aims to use calcium signaling as a functional readout combined with morphological changes to better understand the intracellular and intercellular communication that occurs between glial cells during injury and disease. This study is the first to analyze calcium signaling in NG2-glia during infection and epilepsy development, and may lead to novel cellular and molecular targets to restore homeostasis and prevent the development of epilepsy following a high-risk insult to the central nervous system.

项目概要据 CDC 称，美国有超过 300 万人患有活动性癫痫症。估计高达 50% 的癫痫病例是由神经损伤引发的，称为获得性癫痫。脑感染和创伤性脑损伤是常见脑损伤的两个主要例子，可导致获得性癫痫的发展。尽管该疾病的病因和严重程度存在多样性，了解癫痫发作的细胞和分子机制将有助于发现新的预防高危中枢神经系统损伤后癫痫的方法。越来越多的证据表明神经胶质细胞在启动和维持癫痫发展背后的长期神经可塑性变化。 NG2-神经胶质细胞众所周知作为少突胶质细胞祖细胞（OPC）。然而，越来越多的证据导致了它们的分类作为一种主要的神经胶质细胞类型。最近的证据表明这些细胞在维持环境稳态，以及 NG2-神经胶质细胞功能的破坏现在已被高度关注神经系统疾病的发生和进展。为了研究 NG2-胶质细胞是否参与癫痫的发展，目标 1、NG2-胶质细胞形态、结构在病毒感染诱导的小鼠模型中评估了组织和蛋白质表达癫痫。分析发现 NG2-神经胶质细胞具有高度反应性的形态、增加的增殖，并且参与病毒感染期间和病毒清除后的疤痕形成。这些 NG2-神经胶质反应也高度集中于海马体、活动性感染部位和癫痫发作的起源部位。这是重要的是，虽然可能是由初始感染引发的，但 NG2-神经胶质细胞反应可能会继续发挥作用在导致癫痫的长期神经可塑性缺陷中发挥重要作用。目标 2 中的初步实验表明，细胞外嘌呤（严重损伤信号）病毒感染后在海马中产生的）引起 NG2- 细胞内钙的强烈升高神经胶质细胞。这一发现很重要，因为钙可以用作功能读数，以更好地了解真实的时间动态和环境信号启动 NG2-神经胶质细胞对损伤和感染的反应。未来的工作旨在利用钙信号传导作为功能读数并结合形态变化来更好地理解损伤和疾病期间神经胶质细胞之间发生的细胞内和细胞间通讯。这这项研究首次分析了感染和癫痫发展过程中 NG2 神经胶质细胞中的钙信号传导，并且可能产生新的细胞和分子靶点以恢复体内平衡并预防癫痫的发展中枢神经系统受到高风险损伤后。