Decoding IL-17A-mediated influences on stroke recovery

解码 IL-17A 介导的中风恢复影响

• 批准号: 428778375
• 负责人: Professor Dr. Manuel A. Friese
• 金额: --
• 依托单位: Institut für Neuroimmunologie und Multiple Sklerose (INIMS)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/428778375?language=en
• 关键词: Decoding; IL; 17A; mediated; influences

In stroke, the highly conserved cytokine IL-17A is pivotal for the amplification of the detrimental postischemic inflammatory response in the ischemic tissue. At the same time, IL-17A holds important non-immune properties with trophic and homeostatic effects on neurons and glial cells. Although the immune-pathogenic role of IL-17A has clearly been shown in stroke, it is currently unknown whether different CNS-resident cells differentially sense and react to IL-17A and thereby determine neuronal regeneration. Therefore, the overall objective of the project is to understand how the highly conserved cytokine IL-17A dictates stroke outcome. We aim to decipher the cellular source of IL-17A in the ischemic brain tissue and whether IL-17A dictates neuronal and astrocytic signaling pathways, which alter cellular gene networks that influence neuronal functions. To do so, we will follow the long-term phenotypic outcome after experimental stroke and combine that with cell-type-specific deletions of IL17A and its receptor and cell-type-specific transcriptomics. Eventually, newly assembled gene networks will be validated and mechanistically explored in mouse and human neuronal cell cultures challenged with glutamate and oxygen-glucose deprivation. Thus, we expect to identify neuron-intrinsic genes that are directly regulated by IL-17A or indirectly by astrocytic output after sensing IL-17A and that determine stoke outcome. We envision that these could be potential drug targets to improve post-stroke regeneration.

在中风中，高度保守的细胞因子IL-17A对缺血组织中有害的缺血后炎症反应的扩增至关重要。同时，IL-17A具有重要的非免疫特性，对神经元和神经胶质细胞具有营养和稳态作用。虽然IL-17A在中风中的免疫致病作用已被清楚地证明，但目前尚不清楚不同的中枢驻留细胞是否对IL-17A有不同的感知和反应，从而决定了神经元的再生。因此，该项目的总体目标是了解高度保守的细胞因子IL-17A如何决定中风的结果。我们的目标是破译缺血脑组织中IL-17A的细胞来源，以及IL-17A是否决定神经元和星形细胞信号通路，从而改变影响神经元功能的细胞基因网络。为此，我们将跟踪实验性脑卒中后的长期表型结果，并将其与细胞类型特异性IL17A及其受体缺失和细胞类型特异性转录组学相结合。最终，新组装的基因网络将在谷氨酸和氧-葡萄糖剥夺的小鼠和人类神经元细胞培养中得到验证和机制探索。因此，我们期望确定由IL-17A直接调节或感应IL-17A后星形细胞输出间接调节的神经元内在基因，并确定脑卒中结果。我们设想这些可能是改善中风后再生的潜在药物靶点。