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

• 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
• 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

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.

项目摘要 据疾病预防控制中心（CDC）称，美国有300万人有活跃的癫痫病。据估计 在所有癫痫病例中，多达50％是由神经系统侮辱引发的，被称为获得性癫痫。脑 感染和脑外伤是常见脑损伤的两个主要例子，可能导致 开发后的癫痫。尽管病因学和疾病的严重程度有多样性，但 了解癫痫发育的细胞和分子机制将有助于发现新型 高危中枢神经系统受伤后预防癫痫的方法。 证据积累，表明神经胶质细胞在开始和维持中起重要作用 癫痫发育发展的延长神经塑性变化。 ng2-glia通常是众所周知的 作为少突胶质细胞祖细胞（OPC）。但是，越来越多的证据导致了他们的分类 作为主要的神经胶质细胞类型。最近的证据表明，这些细胞在 维持环境稳态和对NG2-GLIA功能的干扰现已高度含义 在神经系统疾病的发展和发展中。 为了研究NG2-GLIA是否参与癫痫发育，在AIM 1，NG2-GLIA形态，结构性 在病毒感染诱导的获得的小鼠模型中评估了组织和蛋白质表达 癫痫。该分析表明，NG2-GLIA具有高反应性形态，增殖增加，并且是 在病毒感染和病毒清除后涉及疤痕形成。这些NG2-GLIA反应 还高度位于海马，活性感染部位和癫痫发作的起源部位。这是 意义重大，因为虽然可能是由引发感染引发的，但NG2-GLIA反应可能会继续发挥 在导致癫痫的长期神经塑性缺陷中的重要作用。 AIM 2中的初步实验表明细胞外嘌呤（损害信号很大 病毒感染后在海马中产生）诱导NG2-- 神经胶质。这一发现很重要，因为钙可以用作功能读数，以更好地理解实际 时间动力学和环境信号引发了NG2-GLIA对损伤和感染的反应。未来的工作 旨在将钙信号传导用作功能读数以及形态变化以更好地理解 受伤和疾病期间神经胶质细胞之间发生细胞内和细胞间通信。这 研究是第一个在感染和癫痫发育期间分析NG2-GLIA中钙信号传导的研究 导致新型的细胞和分子靶标，以恢复稳态并防止癫痫的发展 在对中枢神经系统的高风险侮辱之后。