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 根据美国疾病控制与预防中心的数据，美国有300多万人患有活动性癫痫。据估计， 高达50%的癫痫病例是由神经侮辱引起的，被称为获得性癫痫。脑区 感染和创伤性脑损伤是常见的脑损伤的两个主要例子，它们可能导致 获得性癫痫的发展。尽管疾病的病因和严重程度各不相同， 了解癫痫发生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，神经胶质细胞在急性髓细胞白血病的发生和维持中起重要作用。 长期的神经可塑性变化是癫痫发生的基础。NG2-神经胶质细胞是众所周知的 作为少突胶质前体细胞(OPC)。然而，越来越多的证据导致了他们的分类 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 维持环境动态平衡和破坏NG2-神经胶质细胞功能现在已经被高度牵连 在神经系统疾病的发展和进展中起重要作用。 为了探讨NG2-胶质细胞是否参与癫痫的发生发展，目的1，NG2-胶质细胞的形态、结构 在病毒感染诱导的获得性小鼠模型中评估组织和蛋白表达 癫痫。分析证明，NG2-胶质细胞具有高度活性的形态，促进了增殖，并 在病毒感染期间和病毒清除后都参与了疤痕的形成。这些NG2神经胶质细胞的反应 也高度定位于海马体，海马体是活跃感染的部位和癫痫发作的起源地。这是 重要的是，虽然可能是由初始感染触发，但NG2-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起着重要作用。 AIM 2的初步实验表明，细胞外的嘌呤(严重的损伤信号 病毒感染后在海马区产生的)诱导NG2-2细胞内钙的强劲升高 神经胶质细胞。这一发现很重要，因为钙可以用作功能读数，以更好地理解真正的 启动NG2-神经胶质细胞对损伤和感染反应的时间动力学和环境信号。下一步工作 旨在使用钙信号作为功能读数，结合形态变化更好地理解 神经胶质细胞在损伤和疾病过程中发生的细胞内和细胞间的通讯。这 这项研究首次分析了NG2-胶质细胞在感染和癫痫发生过程中的钙信号，并可能 引导新的细胞和分子靶点恢复动态平衡和防止癫痫的发展 在中枢神经系统受到高风险的侮辱之后。