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Title: Genetic manipulation of fat in transgenic mice
Author: Felmer, Ricardo
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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The present dissertation describes the use of a novel system to achieve specific cell ablation in fat tissue. The method is based on the use of E.coli nitroreductase (NTR) enzyme that activates certain nitro compounds into cytotoxic DNA interstrand cross-linking agents. This system was assessed first in vitro, in a preadipocyte cell line (3T3L1). Clones of cells that expressed NTR were successfully killed after treatment with CB1954. It was confirmed that the mechanism of cell killing involved is apoptosis and the presence of a cell-permeable metabolite that is released to the medium triggering a bystander effect was observed. This prodrug system was also assessed in vivo, for which transgenic mice were generated expressing NTR specifically in adipose tissue under the control of the aP2 promoter. Upon CB1954 treatment, transgenic mice showed extensive cell depletion in different fat deposits, which was directly correlated to both the dose of prodrug and the levels of NTR expressed. The present model provides a new inducible approach to manipulate the number of adipocytes at different stages of the mouse development and provides a new system for the study of fat metabolism especially in abnormal conditions such as obesity and its modulation through the manipulation of the target cell population. Also reported are preliminary experiments to assess a novel system of ablation mediated by the murine adapter molecule RAIDD. Stable cell lines were generated to overexpress RAIDD after differentiation. A range of phenotypes was observed with these clones from a complete blockage of the differentiation to the killing of cells that escape the blockage. The present results suggest for first time a new developmental role for this gene and strongly encourage further experimentation to confirm this effect in an experimental animal model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available