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Identification of growth signals that cause kidney cyst formation by selectively controlling the orientation but not the rate of cell division

proposé par Mario PENDE, laboratoire : Cell growth control by nutrients, Institut Necker Enfants Malades, Paris 14

Projet de stage : Mammalian Target Of Rapamycin (mTOR) is a master regulator of cell growth present in every eukaryotic cell. mTOR integrates nutrient signals and promotes growth, proliferation, macromolecule biosynthesis. Genetic mutations causing aberrant mTOR activation may trigger benign tumour formation, polycystic kidney disease and epilepsy. However, it is still unclear how kidney cysts and neuronal seizures may arise. Our lab studies mouse and cellular models of the Tuberous Sclerosis Complex disease, in which cystogenesis is accompanied by alterations in the number and angle of cell mitosis. We have identified S6 kinase 1 (S6K1) as an mTOR target required for cyst formation. When we ablate S6K1, we restore oriented cell division and we strongly inhibit the cyst formation, without decreasing the division rate. In this research proposal, the student will investigate this novel role of mTOR/S6K1 signalling in the selective control of oriented cell division. Apico-basal polarity determinants and primary cilia will be assessed by immunofluorescence and gene expression in 3D cultures. Tissue clearing and 3D reconstruction will be also performed in kidneys. 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 cystogenesis. 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 : 2D and 3D confocal microscopy, metabolomics, 3D cultures

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