Role and Function of Microglia Cells in Autoimmune CNS Inflammation

小胶质细胞在自身免疫性中枢神经系统炎症中的作用和功能

• 批准号: 165235933
• 负责人: Professor Dr. Ari Waisman
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/165235933?language=en
• 关键词: Role; Function; Microglia; Cells; Autoimmune

Unlike other glia cells, microglia originate from the myeloid cell lineage and therefore often are considered resident brain macrophages. They act in the first response to direct injury or peripheral insults. However, the exact role microglia play during the process of autoimmune disease in the CNS is not yet clear. In this proposal we suggest the utilization of currently available mouse lines and their combination with newly developed strains to further determine the role of microglia in a mouse model of multiple sclerosis. Focusing on the activation of microglia we will first make use of mouse lines that allow for the conditional deletion of two deubuiquitinating (DUB) enzymes, CYLD and A20, in microglia. As these DUB enzymes normally suppress inflammatory mediators such as the NFκB pathway, their deletion should lead to hyper-activation of microglia. Furthermore we will analyze the role of ionotropic glutamate receptors in microglia activation as rising evidence propose their contribution in the pathogenesis of neuroinflammation and moreover their relevance in microglia activation. In a more generalized approach we will deplete microglia during CNS inflammation and progression and analyze the altered disease outcome.

与其他神经胶质细胞不同，小胶质细胞起源于骨髓细胞谱系，因此通常被认为是常驻脑巨噬细胞。他们在直接伤害或周围侮辱的第一反应。然而，小胶质细胞在CNS自身免疫性疾病过程中的确切作用尚不清楚。在这个提议中，我们建议利用目前可用的小鼠品系及其与新开发的品系的组合，以进一步确定小胶质细胞在多发性硬化症小鼠模型中的作用。专注于小胶质细胞的活化，我们将首先利用允许在小胶质细胞中条件性缺失两种次丁基化（DUB）酶CYLD和A20的小鼠系。由于这些DU B酶通常抑制炎症介质，如NFκB通路，因此其缺失应导致小胶质细胞过度活化。此外，我们将分析离子型谷氨酸受体在小胶质细胞活化中的作用，因为越来越多的证据表明它们在神经炎症的发病机制中的作用，而且它们在小胶质细胞活化中的相关性。在更广泛的方法中，我们将在CNS炎症和进展过程中耗尽小胶质细胞，并分析改变的疾病结局。