Obiettivo Neuronal circuit development involves multiple stages that are regulated by neurotrophic factors. One of the key players, the brain-derived neurotrophic factor (BDNF), is involved in the development and functional modulation of circuits by promoting neuronal survival, synaptogenesis, synaptic transmission and synaptic plasticity. BDNF acts by binding to the tropomyosin-related kinase receptor B (TrkB), a type-I membrane protein, to trigger downstream signaling. However, the molecular architecture of this complex and the mechanism of signal propagation across the membrane remain unknownThe key aim of this project is to define in structural and mechanistic terms the steps leading to TrkB activation upon BDNF binding. I will use X-ray crystallography to determine the structure of the extracellular TrkB-BDNF complex, and validate this model by mutagenesis and biophysical techniques. Single particle cryo-electron microscopy will be used to solve the full-length TrkB-BDNF complex structure. To validate and relate these structures to signaling, structure-based hypotheses will be tested in live cells by fluorescence imaging.Furthermore, to exploit the structural information gained above, I will engineer BDNF molecules with improved physico-chemical properties as well as generate nanobodies against the TrkB extracellular region. These will be screened by biophysical, structural and cellular approaches to evaluate their (i) binding mode and affinity and (ii) ability of promote TrkB activation. Subsequently, collaborative studies in mouse models will test whether these molecules behave as efficient BDNF mimetics in vivo.This multidisciplinary approach will enable me to define determinants of the TrkB-BDNF complex formation, its activation mechanism, and to use this information towards providing a platform for the design of novel tools that target and modulate this crucial signaling pathway, to promote synaptic repair and functional recovery in damaged neuronal circuits. Campo scientifico medical and health sciencesbasic medicineneurologydementiaalzheimermedical and health sciencesbasic medicinephysiologypathophysiologynatural sciencesearth and related environmental sciencesgeologymineralogycrystallographymedical and health sciencesbasic medicineneurologyparkinsonnatural sciencesbiological sciencesmolecular biologystructural biology Programma(i) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Argomento(i) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Invito a presentare proposte H2020-MSCA-IF-2015 Vedi altri progetti per questo bando Meccanismo di finanziamento MSCA-IF-EF-ST - Standard EF Coordinatore UNITED KINGDOM RESEARCH AND INNOVATION Contribution nette de l'UE € 183 454,80 Indirizzo POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon Regno Unito Mostra sulla mappa Regione South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Tipo di attività Research Organisations Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 183 454,80 Partecipanti (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Partecipazione conclusa Regno Unito Contribution nette de l'UE € 0,00 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 Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale Nessun dato