Role of glial-neuronal metabolic communication in autoimmune neuroinflammation

胶质神经元代谢通讯在自身免疫性神经炎症中的作用

• 批准号: 444138499
• 负责人: Dr. Marina Herwerth
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/444138499?language=en
• 关键词: Role; glial; neuronal; metabolic; communication

The metabolic communication between astrocytes and neurons is crucial for neuronal maintenance and survival. Astrocytes supply neurons with energy metabolites, inactivate toxic waste, ensure a constant water equilibrium between extra- and intracellular compartments and exert mediators that modulate signaling pathways in neuroinflammatory environment. Models of astrocytopathy for exploration of neuronal fate in neuroinflammation are lacking. However, Neuromyelitis optica (NMO) is one type of neuroinflammatory disorders that represents a clear astrocytopathy disease. In NMO, patients suffer from severe relapses with poor recovery, resulting in accumulating neurological deficits that are likely due to neuronal damage. Most NMO patients carry a serum autoantibody against Aquaporin-4 (AQP4-Ab), an astrocytic water channel that in the central nervous system (CNS) is expressed in astrocytes. After entry to the CNS, AQP4-Ab damage astrocytes via complement, resulting in astrocyte necrosis. Finally, NMO lesions show demyelination and axon injury. However, how the pathology in NMO spreads beyond initial astrocytopathy leading to neuronal injury and neurodegeneration remains unclear. The involvement of all cell types emphasizes how tightly glia and neurons communicate in the CNS, suggesting that cell death of one cell type has an impact on the others, particularly in the context of neuroinflammation. Here, we propose a research project to investigate glial-neuronal metabolic communication and its possible alterations during neuroinflammation in a mouse model of NMO. Combining innovative biological approaches with cutting-edge methodological tools, we want to investigate the impact of AQP4-Ab mediated neuroinflammation on glial-neuronal communication both on a short- and long-term scale. Hereby, we will address key questions about the metabolic mechanisms underlying neurodegeneration under autoimmune neuroinflammatory conditions. Thus, this project will gain insights into astrocytopathy driven neuronal damage that have a great potential to reveal paradigmatic pathomechanisms in neuroinflammation and thus provide a basis for new therapeutic strategies for various neuroinflammatory diseases.

星形胶质细胞和神经元之间的代谢通讯对于神经元的维持和存活至关重要。星形胶质细胞为神经元提供能量代谢产物，清除有毒废物，确保细胞外和细胞内室之间恒定的水平衡，并在神经炎症环境中发挥调节信号通路的介质。缺乏用于探索神经炎症中神经元命运的星形细胞病模型。然而，视神经肌萎缩症（NMO）是一种神经炎性疾病，代表了一种明确的星形细胞病疾病。在NMO中，患者遭受严重复发，恢复不良，导致可能由于神经元损伤而累积的神经功能缺损。大多数NMO患者携带针对水通道蛋白-4（AQP 4-Ab）的血清自身抗体，水通道蛋白-4是在中枢神经系统（CNS）中在星形胶质细胞中表达的星形胶质细胞水通道。进入CNS后，AQP 4-Ab通过补体损伤星形胶质细胞，导致星形胶质细胞坏死。最后，NMO病变表现为脱髓鞘和轴突损伤。然而，NMO的病理学如何扩散到最初的星形细胞病之外，导致神经元损伤和神经变性仍不清楚。所有细胞类型的参与强调了神经胶质细胞和神经元在CNS中的沟通有多紧密，这表明一种细胞类型的细胞死亡对其他细胞类型有影响，特别是在神经炎症的背景下。在这里，我们提出了一个研究项目，以调查神经胶质-神经元代谢通讯及其可能的改变，在神经炎症的小鼠模型的NMO。将创新的生物学方法与尖端的方法学工具相结合，我们希望在短期和长期范围内研究AQP 4-Ab介导的神经炎症对神经胶质细胞-神经元通信的影响。在此，我们将解决关键问题的代谢机制下的自身免疫性神经炎症条件下的神经变性。因此，该项目将深入了解星形细胞病驱动的神经元损伤，这些损伤具有很大的潜力来揭示神经炎症的典型病理机制，从而为各种神经炎症性疾病的新治疗策略提供基础。