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Spatio-temporally-controlled somatic mutagenesis of the rxra, rary andrara genes in the mouse epidermis - role of retinoid receptors in epidermis homeostasis, wound healing and other physiopathological

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Research objectives and content
The effects of retinoids are mediated by two types of ligand activated receptors, the Retinoid Acid Receptor (RARa, RARa and RARy and the Retinoid X Receptors (RXRa, RARa and RARy Previous transgenic approaches have resulted in mice in which the epidermally expressed RARa, RARy or RARa are deficient. These mice showed either no significant alteration of the epidermal morphology (RARa and RARy) or embryonic lethality (RXRa).In this project we contemplate to create mouse lines, which will allow us to knockout the RXRa RARa and RARy genes at a given time in different cell types of the epidermal layers. We will construct mice strains carrying functional retinoid receptor genes, but with loxP-flanked exons. Intercrossing of these strains with transgenic strains carrying a tamoxifen-inducible Cre recombinase under the control of a cell- specific promoter will allow the activation of the Cre recombinase in a tamoxifen-dependent manner at a given age of the animals in given cell layers, thus generating spatio-temporally controlled somatic mutations. Training content (objective, benefit and expected impact)
This study should provide new insights into the role of retinoid receptors in epidermis homeostasis, wound healing and mechanisms implicated in retinoid treatment of some skin disorders. This project makes it possible to learn the new mouse genetics, which is particularly important for the investigation of protein functions in vivo and the elucidation of vertebrate development and physiology at the molecular level. Links with industry / industrial relevance (22)
Mouse genetics is indispensable for generating animal models of human diseases. These models will be ofparamount importance in the post-genomic era. The IGBMC receives synthetic retinoids from BristolMyers Squibb.

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Finanzierungsplan

RGI - Research grants (individual fellowships)

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CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
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