Contribución de la vía de PDK1 a la supervicencia y diferenciación neuronales: caracterización de ratones knopck-in de PDK1 específicaos de neurona

Project Details

Description

The main goal of this project is to elucidate the relative contribution of the different PKB isoforms to neuronal survival and differentiation when compared with that of other PDK1 substrates. To achieve that, conditional knock-in mice specifically expressing in the nervous system mutated forms of PDK1 which are not longer able to activate:1) the PKB isoforms, and 2) the rest of PDK1 substrates (p70S6K, SGK, p90rsk, and PKC isoforms) will be employed.
I will first characterise the phenotype of those mice. Anatomical and histological analysis of the overall architecture of the central nervous system will be intensely characterised, and cell size, number and morphology will be scored. Special attention will be devoted to the physiology and behaviour of the PDK1 conditional knock-in mice. I will then investigate the role of the PDK1 substrates in survival and differentiation of these neuronal primary cultures upon stimulation with neurotrophic factors, after cellular stress and upon induction of apoptosis. The involvement of the PDK1 substrates in the intracellular signalling pathways induced by neurotrophic factors will be studied. To that end , I will measure the activities of the PDK1-regulated kinases ans will analyse the phosphorylation levels of those PKB physiologic targets involved in cellular survival, such as FOXO1, CREB, GSK3, BAD and IKK, and the phosphorylation levels of the p70S6K targets involved in protein synthesis and cell growth control, as it is the case of the S6 protein and 4E-BP1.
StatusFinished
Effective start/end date16/10/0730/12/10

Funding

  • Instituto de Salud "Carlos III": €174,240.00

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