Induzierbare Ablation von Mikroglia

在许多神经系统疾病中，小胶质细胞被激活。我建议建立一个动物模型，在这个模型中，小胶质细胞可以被有条件地消融，以研究它在健康和疾病中的作用。对于有条件的小胶质细胞消融，我将在巨噬细胞特异性CD11b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，它们会遇到同源配体(FRB-LNGFR)，我将在NSE启动子控制下的神经元上表达FRB-LNGFR。只有当给予FKBP-FRB二聚化Rapalog时，嵌合受体和配体才会发生相互作用，并触发Fas介导的细胞凋亡。除了在实验性神经病理学中的作用外，该系统还可以很容易地进行修改，根据与其他给定细胞的相互作用，介导任何给定细胞类型的药物控制的凋亡。小胶质细胞被认为在TSEx(传播性海绵状脑病)的病理过程中起重要作用。我将使用这个动物模型来研究小胶质细胞在Pron病中的作用。我将用RML蛋白感染我的转基因小鼠，并分析大脑病理。这个模型应该允许在不同的疾病阶段消融小胶质细胞，从而能够精确地剖析其在普恩病毒传播和神经发病中的作用。

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.