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: 10704766
• 负责人: Laura Ann Bell
• 金额: $ 8.45万
• 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: 2021-09-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704766
• 关键词: Investigating; role; NG2; glia; development

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CDC的数据，美国有超过300万人患有活动性癫痫。据估计 高达50%的癫痫病例是由神经损伤引起的，称为获得性癫痫。大脑 感染和创伤性脑损伤是常见脑损伤的两个主要例子， 获得性癫痫的发展。虽然在病因和疾病的严重程度上存在多样性， 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，胶质细胞在启动和维持神经元凋亡中起重要作用。 神经可塑性的长期变化是癫痫发生的基础。NG 2-神经胶质细胞是众所周知的 作为少突胶质祖细胞（OPCs）。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。最近的证据表明，这些细胞在 维持环境稳态和破坏NG 2-胶质细胞功能现在已经高度牵连 在神经系统疾病的发展和进展中的作用。 为了研究NG 2-胶质细胞是否参与癫痫的发生发展，目的1，NG 2-胶质细胞的形态学、结构和功能变化， 在病毒感染诱导的获得性免疫缺陷小鼠模型中评估了组织和蛋白质表达。 癫痫分析表明NG 2-胶质细胞具有高度反应性的形态，增殖增加， 在病毒感染期间和病毒清除之后都参与瘢痕形成。这些NG 2神经胶质细胞的反应 也高度定位于海马体，活跃感染的部位和癫痫发作的起源部位。这是 重要的是，虽然可能由初始感染触发，但NG 2-胶质反应可能继续发挥作用 在导致癫痫的长期神经可塑性缺陷中起重要作用。 目的2中的初步实验表明，细胞外嘌呤（损伤严重受损的信号） 在病毒感染后海马中产生的）诱导NG 2 - 1细胞内钙的强烈升高。 神经胶质。这一发现很重要，因为钙可以作为一个功能读数，以更好地了解真实的- 时间动力学和环境信号引发NG 2-胶质细胞对损伤和感染的反应。今后工作 目的是利用钙信号作为功能读数结合形态学变化，以更好地了解 在损伤和疾病期间发生在神经胶质细胞之间的细胞内和细胞间通讯。这 这项研究是第一个分析感染和癫痫发展过程中NG 2-胶质细胞钙信号传导的研究， 导致新的细胞和分子靶点，以恢复体内平衡和预防癫痫的发展 在中枢神经系统受到高风险损伤后死亡