Obiettivo 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. Campo scientifico engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensorsmedical and health sciencesclinical medicineoncologymedical and health sciencesbasic medicinephysiologyhomeostasisnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Parole chiave Hypoxia hypoxic response iron-oxygenase ischemic disease oxygen oxygen-sensing post-translational modification transcriptional regulation Programma(i) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) ERC-AG-LS1 - ERC Advanced Grant - Molecular and Structural Biology and Biochemistry Invito a presentare proposte ERC-2008-AdG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-AG - ERC Advanced Grant Istituzione ospitante THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Contributo UE € 3 000 000,00 Indirizzo WELLINGTON SQUARE UNIVERSITY OFFICES OX1 2JD Oxford Regno Unito Mostra sulla mappa Regione South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Stephen Conway (Dr.) Ricercatore principale Christopher Joseph Schofield (Prof.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Regno Unito Contributo UE € 3 000 000,00 Indirizzo WELLINGTON SQUARE UNIVERSITY OFFICES OX1 2JD Oxford Mostra sulla mappa Regione South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Stephen Conway (Dr.) Ricercatore principale Christopher Joseph Schofield (Prof.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
