The Role of Monocytic Cells in Long-Term Post-Stroke Outcome

单核细胞在中风后长期结果中的作用

• 批准号: 397020466
• 负责人: Professorin Dr. Karen Gertz, since 7/2018
• 金额: --
• 依托单位: Klinik für Neurologie mit Experimenteller Neurologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/397020466?language=en
• 关键词: Role; Monocytic; Cells; Long; Term

The translational roadblock in stroke research may in part relate to the fact that the interplay of different pathomechanisms is more complex than previously thought. In particular, inflammatory processes which are involved in cellular damage during the early phase of brain ischemia may promote recovery at later stages. Our proposal tests the hypothesis that the pathogenetic role of resident microglia versus invading monocytes diverges markedly and changes time-dependently after brain ischemia. We will use bone-marrow (BM) chimerism, viral vectors, and genetically modified mice (e.g. Ccr2RFP::Cx3cr1GFP mice) to study differences between microglia and invading monocytes. In dual-color experiments, we will trace the influx of red fluorescently labeled monocytes into the ischemic brain of mice harboring microglia expressing GFP (MacGreen mouse model). This approach not only permits convenient detection of microglia and invaded macrophages for histological and physiological analyses, but also facilitates isolation for functional assays and transcriptional profiling. Then, we will interfere with the invasion of inflammatory cells into the brain using genetically altered BM (e.g. gelsolin-deficient BM resulting in impaired migration into ischemic brain parenchyma, P-selectin glycoprotein ligand-1 [PSGL-1] deficient BM resulting in impaired tethering/adhesion). We will specifically focus on complex endpoints including secondary neurodegeneration, cellular plasticity and neurobehavioral outcomes.

中风研究中的转化障碍可能部分与不同病理机制的相互作用比以前认为的更复杂这一事实有关。特别是，在脑缺血的早期阶段参与细胞损伤的炎症过程可能促进后期阶段的恢复。我们的建议测试的假设，居民小胶质细胞与入侵单核细胞的致病作用明显分歧，并改变脑缺血后的时间依赖性。我们将使用骨髓（BM）嵌合体、病毒载体和基因修饰小鼠（例如Ccr 2 RFP：：Cx 3cr 1GFP小鼠）来研究小胶质细胞和入侵单核细胞之间的差异。在双色实验中，我们将追踪红色荧光标记的单核细胞流入含有表达GFP的小胶质细胞的小鼠（MacGreen小鼠模型）的缺血脑中。这种方法不仅可以方便地检测小胶质细胞和侵入的巨噬细胞的组织学和生理学分析，但也有利于分离功能测定和转录谱。然后，我们将使用基因改变的BM（例如，凝溶胶蛋白缺陷BM导致向缺血性脑实质的迁移受损，P-选择素糖蛋白配体-1（PSGL-1）缺陷BM导致束缚/粘附受损）干扰炎性细胞侵入脑。我们将特别关注复杂的终点，包括继发性神经变性，细胞可塑性和神经行为结果。