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> Stages de M2 > stages proposés pour l’année 2019-2020 > Control of neuronal size, plasticity and excitability in genetic models of (...)

Control of neuronal size, plasticity and excitability in genetic models of mTORopathy

proposé par Mario PENDE, , Inserm U1151, Institut Necker, 75015 Paris

Projet de stage : The mammalian Target Of Rapamycin (mTOR) kinase is a master regulator of cell growth present in every eukaryotic cell, from unicellular organisms to humans. This conserved and fundamental role stems from mTOR ability to integrate nutritional cues, coordinate macromolecule biosynthesis, and control cell number and size. Strikingly, genetic diseases leading to the up-regulation of mTOR activity predispose to malformations of cortical brain development, now classified as mTORopathies, which are associated with epilepsy as well as intellectual disability and autism. Our preliminary data identified one mTOR substrate, S6 kinases 1 (S6K1), as an essential factor for cortical malformations and seizures in a mouse model of mTORopathy. Since the overactivation of S6K1 is accompanied by hallmarks of senescence, we hypothesize that an alteration of the balance between programmed cell death and senescence during postnatal development may contribute to persistent connectivity, miswiring and excitability. In this research proposal, the student will analyze cellular plasticity, development and single transduction to identify the novel therapeutic targets involved in neuronal function and disease. The student will be part of a team in which phospho-proteomics, metabolomics and genome editing approaches are taken to discover the functional substrate of S6K1 involved in neuronal plasticity. The student will profit of state-of-the-art facilities and research interests spanning from cell biology, human disease, signal transduction, metabolism. The work environment is international and multi-lingual.

Techniques mises en œuvre par le stagiaire : Histology, gene expression studies, metabolomics

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