Objectif
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.
Champ scientifique
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesbasic medicineneurologyepilepsy
- medical and health sciencesbasic medicineneurologymuscular dystrophies
- medical and health sciencesbasic medicinemedicinal chemistry
- medical and health sciencesclinical medicinepsychiatryschizophrenia
Mots‑clés
Appel à propositions
FP7-HEALTH-2007-A
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Régime de financement
CP-IP - Large-scale integrating projectCoordinateur
1081 HV Amsterdam
Pays-Bas
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Participants (23)
1066 CX Amsterdam
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3000 Leuven
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91054 Erlangen
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CB2 1TN Cambridge
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1090 Wien
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75724 Paris
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117997 MOSCOW
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75654 Paris
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69117 Heidelberg
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WC1E 6BT LONDON
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1211 Geneve
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00185 Roma
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11521 Athens
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265 04 Rio Patras
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78464 Konstanz
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55129 MAINZ
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17455 ATHENS
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754 50 Uppsala
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1008 BA AMSTERDAM
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41121 Modena
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10561 Athina
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1211-12 GENEVE
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1081 HV Amsterdam
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