Zabel
Fakultäten » Medizinische Fakultät » Neuropathologie, Institut für » Prof. Dr. Adriano Aguzzi » Zabel
Completed research project
| Title / Titel | Using cell contact-mediated ablation of microglia to decipher their role in prion pathogenesis | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | No technology exists that conditionally modifies gene expression and/or cellular function based on the environment in which specific cell types reside. For example, macrophages, Kupffer cells, and microglia reside in different compartments of the body, yet belong to the same lineage: as of now there is no way to achieve transgenic expression in one of these cell types but not in the others. The usefulness of such paradigms would be obvious and broadly adaptable to questions of neurobiology, cancer research, developmental biology, and many others. We plan to provide proof-of-principle in the area of neurodegenerative diseases. Animal models that allow for the specific ablation of microglia would greatly facilitate the determination of its role in the pathology of transmissible spongiform encephalopathies (TSEs). TSEs are neurodegenerative disorders that include scrapie in sheep and goats; bovine spongiform encephalopathy (BSE) in cattle; and Creutzfeldt-Jakob disease (CJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI) in humans (1). A dominant feature of TSEs are spongiform changes observed on histological sections of the brain. It is not yet clear how this cellular damage of neurons is mediated, but a large body of evidence suggests a crucial role of microglia in pathogenesis. Microglia accumulation and activation has been shown to parallel the temporal and spatial pattern of PrPSc deposition and precedes neuronal vacuolization and cell death (2-4). Moreover, in spongiform encephalopathies microglia accumulate at affected brain areas(3-5). 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 similar diseases. Since no microglial-specific promoters are known, current technologies fail to accomplish this goal. This proposal provides means by which microglia can be selectively ablated based on its environment, i.e., the cells that they contact. Contact-dependent switches: technical background To specifically eliminate microglia, we propose here a method for ablating microglial in the mouse brain. This method relies on the construction of a chimeric protein consisting of a transmembrane receptor and a toxin. A second protein encoding the ligand will be expressed on a cell, in this case astrocytes, that interacts with the target cell. This model offers the ability to tightly control a potent toxin that uses a universal killing mechanism applicable to a wide variety of cell types. It is thinkable to apply this system to a much broader set of questions related to the conditional expression of any gene in any specific cell type dependent on its contact with another specified cell type. |
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| Keywords / Suchbegriffe | microglia, Notch, Delta, CdtB, brain, GFAP, CD11b, astrocyte, prion | ||||
| 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 |
Foundation, Others HFSP, Volkswagen-Stiftung |
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| Duration of Project / Projektdauer | Mar 2002 to Feb 2006 |