Zeller
Fakultäten » Medizinische Fakultät » Neuropathologie, Institut für » Prof. Dr. Adriano Aguzzi » Zeller
Completed research project
| Title / Titel | Investigation of the role of microglia in Prion disease by cell specific ablation of microglia in vivo | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of the central nervous system which are histologically characterized by spongiform degeneration of the brain parenchyma, or neuronal degeneration and death, and astrocytosis of the brain. It remains unclear how this neuronal damage is mediated, but evidence points to a potential crucial role for microglia. Microglial accumulation and activation parallels the temporal and spatial pattern of PrpSc deposition and precedes neuronal vacuolisation and cell death. Moreover, microglia accumulation coincides with sites of neuronal loss. Although microglia become activated in these and other neurological diseases, their protective or pathological function remains poorly understood. Specific ablation of microglia would significantly help to determine their function in brains of mice afflicted with prion- or other neurodegenerative diseases. A transgenic mouse model will be developed in which microglia will be ablated specifically, while monocytes and fixed tissue macrophages outside of the CNS remain unaffected. A suicide switch will be expressed specifically in monocytes/macrophages under the control of the CD11b-promoter. To specifically ablate microglia only, a CNS specific second signal from the astrocyte leads to the induction of microglial death. Thus a monocyte will die as soon as it enters the brain to become a microglia cell. Two strategies will be attempted to ablate the microglia: The first approach is based on chemical induced dimerization. Here a chimeric receptor construct known as FKBP-Fas will be expressed under the control of the monocyte specific CD11b promoter and therefore will be present on macrophages. The cognate ligand FRB, will be expressed on astrocytes under the control of the GFAP-promoter. Only when the FKBP-FRB dimerizing agent is administered, interaction of chimeric receptors and ligands will occur and trigger Fas-mediated apoptosis of the microglial cell. The second approach employs the Cre-lox-system. In the first phase of this project, the subunit A of Diphtheria toxin will be expressed under the control of the CD11b promoter, ensuring specificity for cells of the macrophage lineage. A transcriptional Stop-signal, flanked by two loxP recombination sites will be inserted 5` to the dta-gene. Next a secretable form of the Cre-recombinase will be expressed specifically by astrocytes under the control of the GFAP-promoter. Therefore, either the constitutive or conditional expression of secretable Cre by astrocytes will lead to the excision of the stop signal and subsequent DT-A expression under control of the CD11b-promoter. The DT-A specifically leads to microglial death. |
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| Keywords / Suchbegriffe | Cell ablation, chemical induced dimerization, Cre-lox, DT-A | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Other links to external web pages | http://www.uzh.ch/pathol/neuropathologie/d/index.html | ||||
| Funding source(s) / Unterstützt durch |
Others |
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| Duration of Project / Projektdauer | Mar 2002 to Feb 2005 |