Induzierbare Ablation von Mikroglia

小胶质细胞诱导消融

• 批准号: 5396337
• 负责人: Dr. Judith Gottwein
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2003
• 资助国家: 德国
• 起止时间: 2002-12-31 至 2003-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5396337?language=en
• 关键词: Induzierbare; Ablation; von; Mikroglia

Microglia becomes activated in many neurological diseases. I propose to develop an animal model in which microglia can be ablated conditionally in order to study its role in health and disease. For conditional ablation of microglia, I will express a death switch (FKBP-Fas) under control of the macrophage-specific CD11b promoter. When macrophages enter the brain they will encounter the cognate ligand (FRB-LNGFR), which I will express on neurons under control of the NSE promoter. Only when the FKBP-FRB dimerizing rapalog is administered, interaction of chimeric receptors and ligands will occur and trigger Fas-mediated apoptosis. In addition to its usefulness in experimental neuropathology, this system can be easily modified to mediate pharmacologically controlled apoptosis of any given cell type depending of interactions with other given cells. Microglia is suspected to play an important role in the pathology of TSEx (transmissible spongiform encephalopathies). I will use this animal model to investigate the role of microglia in prion disease. I will infect my transgenic mice with RML prions and analyse brain pathology. This model should allow for ablation of microglia at various disease stages, therefore enabling a precise dissection of its role in prion propagation and neuropathogenesis.

小胶质细胞在许多神经系统疾病中被激活。我建议开发一种动物模型，其中小胶质细胞可以有条件地消融，以研究其在健康和疾病中的作用。对于小胶质细胞的条件性消融，我将在巨噬细胞特异性CD 11b启动子的控制下表达死亡开关（FKBP-Fas）。当巨噬细胞进入大脑时，它们将遇到同源配体（FRB-LNGFR），它将在NSE启动子的控制下在神经元上表达。只有当施用FKBP-FRB二聚化雷帕霉素时，嵌合受体和配体的相互作用才会发生并触发Fas介导的细胞凋亡。除了其在实验神经病理学中的有用性之外，该系统可以容易地被修改以根据与其他给定细胞的相互作用来介导任何给定细胞类型的细胞凋亡。小胶质细胞被怀疑在TSEx（传染性海绵状脑病）的病理学中发挥重要作用。我将使用这个动物模型来研究小胶质细胞在朊病毒疾病中的作用。我将用RML朊病毒感染我的转基因小鼠，并分析大脑病理学。该模型应允许消融的小胶质细胞在不同的疾病阶段，因此，使其在朊病毒传播和神经发病机制的作用的精确解剖。