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Neurotransmitter Cys-loop receptors: structure, function and disease

Neurotransmitter Cys-loop receptors: structure, function and disease

Objective

Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimer’s and Parkinson’s, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function. A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.
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Coordinator

STICHTING VU

Address

De Boelelaan 1105
1081 Hv Amsterdam

Netherlands

Activity type

Higher or Secondary Education Establishments

Administrative Contact

Yvonne Kops (Dr.)

Participants (23)

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STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS

Netherlands

EU Contribution

€ 768 965,20

KATHOLIEKE UNIVERSITEIT LEUVEN

Belgium

EU Contribution

€ 566 671,60

FRIEDRICH-ALEXANDER-UNIVERSITAET ERLANGEN NUERNBERG

Germany

EU Contribution

€ 505 483,60

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE

United Kingdom

EU Contribution

€ 528 430

MEDIZINISCHE UNIVERSITAET WIEN

Austria

EU Contribution

€ 536 077,60

INSTITUT PASTEUR

France

EU Contribution

€ 613 424,80

SHEMYAKIN AND OVCHINNIKOV INSTITUTE OF BIOORGANIC CHEMISTRY - RUSSIAN ACADEMY OF SCIENCE

Russia

EU Contribution

€ 675 484

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France

EU Contribution

€ 514 000

EUROPEAN MOLECULAR BIOLOGY LABORATORY

Germany

EU Contribution

€ 255 000

UNIVERSITY COLLEGE LONDON

United Kingdom

EU Contribution

€ 503 797

UNIVERSITE DE GENEVE

Switzerland

EU Contribution

€ 200 409,60

CONSIGLIO NAZIONALE DELLE RICERCHE

Italy

EU Contribution

€ 320 400

HELLENIC PASTEUR INSTITUTE

Greece

EU Contribution

€ 736 600

PANEPISTIMIO PATRON

Greece

EU Contribution

€ 581 969,20

UNIVERSITAT KONSTANZ

Germany

EU Contribution

€ 581 920

PROTEOSYS AG

Germany

EU Contribution

€ 114 999,60

REGULON AE

Greece

EU Contribution

€ 125 628,26

BEACTICA AB

Sweden

EU Contribution

€ 355 190,40

SYNAPTOLOGICS BV

Netherlands

EU Contribution

€ 497 599,96

UNIVERSITA DEGLI STUDI DI MODENA E REGGIO EMILIA

Italy

EU Contribution

€ 120 000

ETHNIKO KAI KAPODISTRIAKO PANEPISTIMIO ATHINON

Greece

EU Contribution

€ 134 291,78

HIQSCREEN SARL

Switzerland

EU Contribution

€ 243 990,40

VERENIGING VOOR CHRISTELIJK HOGER ONDERWIJS WETENSCHAPPELIJK ONDERZOEK EN PATIENTENZORG

Netherlands

EU Contribution

€ 1 544 667

Project information

Grant agreement ID: 202088

Status

Closed project

  • Start date

    1 February 2008

  • End date

    31 July 2012

Funded under:

FP7-HEALTH

  • Overall budget:

    € 14 640 209,20

  • EU contribution

    € 11 025 000

Coordinated by:

STICHTING VU

Netherlands