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Molecular Mechanism of Oxygen Sensing by Enzymes

Objectif

The hypoxic response in humans is regulated by enzymes that catalyse the post-translational hydroxylation of hypoxia inducible factor (HIF). Prolyl-hydroxylation signals for HIF-alpha degradation whilst asparaginyl-hydroxylation blocks the transcriptional activity of HIF. The absolute requirement of the HIF hydroxylases for oxygen enables them to act as hypoxia sensors. The overall goal of the proposed programme is to capitalize on recent advances in this field arising from the joint Schofield and Ratcliffe laboratories, in a multidisciplinary chemistry-biology approach aimed at opening new horizons both for the basic molecular understanding, and for the therapeutic manipulation, of the human transcriptional response to hypoxia. The specific objectives of the proposed programme will be pursued via defined and syngergistic work packages and include (i) To develop and apply state-of-the-art methods for monitoring oxygen-dependant hydroxylation within cells that will enable us to examine the role of the hydroxylases as signal integration points for redox factors; (ii) To define the existence and nature of the structural and kinetic features that underpin the physiological function of HIF hydroxylases in oxygen homeostasis; (iii) To define the extent and biological roles of post-translational hydroxylation in human cells; (iv) To develop novel templates for selective inhibition and activation of individual human HIF hydroxylases. We will follow a multidisciplinary approach ranging from kinetic and high-resolution structural analyses on the hydroxylases to studies in animal cells. We aim that the results will not only be of use in ongoing pharmaceutical attempts to modulate the natural hypoxic response for the treatment of ischemic disease and cancer, but will serve as a paradigm for biomedicinal analyses of signalling systems.

Appel à propositions

ERC-2008-AdG
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Régime de financement

ERC-AG - ERC Advanced Grant

Institution d’accueil

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Adresse
Wellington Square University Offices
OX1 2JD Oxford
United Kingdom

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Type d’activité
Higher or Secondary Education Establishments
Contact administratif
Stephen Conway (Dr.)
Chercheur principal
Christopher Joseph Schofield (Prof.)
Contribution de l’UE
€ 3 000 000

Bénéficiaires (1)

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
Contribution de l’UE
€ 3 000 000
Adresse
Wellington Square University Offices
OX1 2JD Oxford

Voir sur la carte

Type d’activité
Higher or Secondary Education Establishments
Contact administratif
Stephen Conway (Dr.)
Chercheur principal
Christopher Joseph Schofield (Prof.)