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Cell growth control by nutrients

Cell growth control by nutrients

Objective

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.

Principal Investigator

Mario Pende (Dr.)

Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Address

Rue De Tolbiac 101
75654 Paris

France

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 831 200

Principal Investigator

Mario Pende (Dr.)

Administrative Contact

Nicolas Jeanjean (Mr.)

Beneficiaries (1)

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INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France

EU Contribution

€ 831 200

Project information

Grant agreement ID: 204486

Status

Closed project

  • Start date

    1 October 2008

  • End date

    30 September 2012

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 831 200

  • EU contribution

    € 831 200

Hosted by:

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France