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STrkB

The structural biology of TrkB-BDNF signalling

Total Cost €

0

EC-Contrib. €

0

Partnership

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 STrkB project word cloud

Explore the words cloud of the STrkB project. It provides you a very rough idea of what is the project "STrkB" about.

bdnf    mutagenesis    downstream    modulation    molecules    structure    receptor    stages    techniques    signal    synaptic    trigger    plasticity    functional    binding    region    membrane    electron    cells    live    nanobodies    protein    architecture    determinants    efficient    synaptogenesis    screened    behave    models    mechanistic    hypotheses    structures    circuit    regulated    tools    physico    tested    gained    brain    collaborative    full    crystallography    acts    particle    model    structural    biophysical    extracellular    unknown    relate    chemical    kinase    length    neuronal    modulate    me    vivo    signaling    tropomyosin    transmission    circuits    cellular    imaging    platform    mimetics    players    engineer    activation    single    affinity    propagation    multidisciplinary    subsequently    trkb    mechanism    cryo    recovery    molecular    repair    survival    generate    multiple    mode    microscopy    ray    validate    damaged    fluorescence    neurotrophic    mouse   

Project "STrkB" data sheet

The following table provides information about the project.

Coordinator
UNITED KINGDOM RESEARCH AND INNOVATION 

There are not information about this coordinator. Please contact Fabio for more information, thanks.

 Coordinator Country United Kingdom [UK]
 Project website https://www2.mrc-lmb.cam.ac.uk/group-leaders/a-to-g/radu-aricescu/
 Total cost 183˙454 €
 EC max contribution 183˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2015
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2017
 Duration (year-month-day) from 2017-07-01   to  2019-06-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNITED KINGDOM RESEARCH AND INNOVATION UK (SWINDON) coordinator 183˙454.00
2    MEDICAL RESEARCH COUNCIL UK (SWINDON) coordinator 0.00
3    THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD UK (OXFORD) participant 0.00

Map

 Project objective

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 unknown The 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.

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The information about "STRKB" are provided by the European Opendata Portal: CORDIS opendata.

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