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Cell growth control by nutrients

Mammalian Target Of Rapamycin (mTOR) is an evolutionary conserved protein kinase that integrates signals from growth factors, nutrients and cellular energy status to regulate cell proliferation, survival, growth and metabolism. mT... ver más

30/09/2012

INSERM

831K€

Presupuesto del proyecto: 831K€

Líder del proyecto

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

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Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2012-09-30 No tenemos la información de la convocatoria

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Líder del proyecto

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 831K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Mammalian Target Of Rapamycin (mTOR) is an evolutionary conserved protein kinase that integrates signals from growth factors, nutrients and cellular energy status to regulate cell proliferation, survival, growth and metabolism. mTOR functions have been inferred so far by employing rapamycin, an inhibitor that has therapeutical uses as immunosuppressive and anti cancer agent. However rapamycin is not a general mTOR inhibitor because mTOR is part of at least two distinct multiprotein complexes, one of which is rapamycin insensitive. Thus genetic approaches are needed to study the full spectrum of mTOR functions on growth and metabolism. We analyse mouse lines carrying inactivating mutations in the mTOR signaling pathway. The muscle specific mTOR knockout mice show a dramatic phenotype, as they develop a severe muscular dystrophy providing an animal model of myopathy. These preliminary data indicate a novel link between mTOR signaling deregulation and the development of muscular dystrophy. In addition we have demonstrated that the inactivation of the mTOR substrate S6 kinase 1 (S6K1) is sufficient to trigger muscle atrophy. Our future research aims at identifying the causes of these dystrophic and atrophic phenotypes in mammalian tissues. In collaboration with the Medical Genetics department at the Necker Hospital we are setting up a functional screening of muscle samples from myopathic patients to search for mutations in the mTOR pathways. We will establish primary myoblast cultures from muscle biopsies and evaluate the activities of the distinct mTOR effectors. This rapid analysis should restrict the number of candidate alleles to be sequenced. We predict that defects in the mTOR pathway should underlie a broad range of orphan myopathy diseases, potentially opening new strategies for diagnosis and therapy of skeletal muscle pathologies. Finally we will use gain of function mutants and in vivo gene therapy to address the role of this pathway in cancer progression.

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