Induzierbare Ablation von Mikroglia

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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.