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GSK-3 in neuronal plasticity and neurodegeneration: basic mechanisms and pre-clinical assessment

Objective

Neuronal circuits in mammalian brain act predominantly via excitatory synapses on dendritic spines. Formation of new spines in adult brain constitutes the structural basis of neuronal plasticity. The underlying molecular mechanisms remain largely unknown but depend essentially on kinase-dependent signalling pathways. Final formation of synapses on spines depends on dynamic interactions of microtubuli and actin-filaments that are also controlled by kinases. Deterioration of these processes to different extents are thought to cause the cognitive decline in normal ageing as well in Alzheimer's disease (AD) and familial fronto-temporal dementia (FTD). Protein tau is a microtubule associated protein and GSK-3 kinases are proposed as the major tau-kinases in vivo. Their exact contributions remain to be functionally defined in vivo both in normal neuronal plasticity and in degeneration. We develop pre-clinical models for AD and FTD that have tauopathy in common as essential pathogenic component and will explore the GSK-3 kinases in vivo by manipulating their activity genetically, pharmacologically and biochemically. Inhibitors are wanted that are effective and specific and enter brain in vivo. This proposal engages in three activities: (i) elucidate physiological functions of GSK-3 kinases in synaptic plasticity in adult and ageing brain, and in degenerating brain; define fundamental neuron-specific functions of GSK-3 kinases in vivo in novel mouse models; define contributions of GSK-3 kinases to amyloid and to tau pathology, separately and combined in vivo in validated mouse models (ii) design novel inhibitors of GSK-3 kinases and alternative tools to inhibit GSK-3 activity in vivo (iii) test pharmacological and peptidometic inhibitors of GSK-3 in validated mouse models of neurodegeneration for their restorative potential; analyse their mode of action and their acute and chronic effects by multi-parametric analysis

Call for proposal

FP7-HEALTH-2007-B
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Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

KATHOLIEKE UNIVERSITEIT LEUVEN
Address
Oude Markt 13
3000 Leuven
Belgium
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 865 280
Administrative Contact
Tine Heylen (Ms.)

Participants (6)

MEDICAL RESEARCH COUNCIL
United Kingdom
EU contribution
€ 342 870
Address
North Star Avenue Polaris House 2 Floor David Phillips Building
SN2 1FL Swindon
Activity type
Research Organisations
Administrative Contact
Elizabeth Cutler (Ms.)
TEL AVIV UNIVERSITY
Israel
EU contribution
€ 487 600
Address
Ramat Aviv
69978 Tel Aviv
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Lea Pais (Ms.)
LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Germany
EU contribution
€ 671 600
Address
Geschwister Scholl Platz 1
80539 Muenchen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Jochen Herms (Prof.)
TECHNISCHE UNIVERSITAT DARMSTADT
Germany
EU contribution
€ 370 968
Address
Karolinenplatz 5
64289 Darmstadt
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Boris Schmidt (Prof.)
INTERNATIONAL INSTITUTE OF MOLECULAR AND CELL BIOLOGY
Poland
EU contribution
€ 280 840
Address
Ks. Trojdena 4
02-109 Warsaw
Activity type
Research Organisations
Administrative Contact
Urszula Wyrzykowska (Dr.)
NOSCIRA SA
Spain
EU contribution
€ 554 684
Address
Calle Jose Abascal 2
28003 Madrid
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Rebeca García (Ms.)