Project full title:
Targeting of stress kinase signalling as a therapeutic strategy against excitotoxicity
Excitotoxicity
(EXC), neuronal death from excessive stimulation, contributes to a
plethora of neurodegenerative diseases and conditions including cerebral ischemia (stroke)
and seizure-induced death (epilepsy). Stress activated protein kinases (SAPKs)
of the c-Jun N-terminal kinases (JNK) and p38 families have been identified as novel mediators
of EXC death which is mainly executed by post-translational modification of existing proteins.
The STRESSPROTECT members - research groups led by Thomas Herdegen, Christophe Bonny, Vincent Castagné, Peter G. H. Clarke, Eleanor Coffey, Michael J. Courtney, Giles E. Hardingham and Alessandro Vercelli - have
- (a) demonstrated that specific TAT-fused peptide inhibitors of the JNK pathway confer lasting neuroprotection against seizure-induced and ischemic cell death with an extended therapeutic time-window,
- (b) analysed the individual apoptotic actions of SAPK isoforms, and
- (c) provided important insights into signalling from glutamate-receptors (e.g. NMDA receptor).
STRESSPROTECT brings together
European laboratories studying SAPK signalling in the
brain and the neuroprotective effects of SAPK inhibitors against EXC.
STRESSPROTECT provides synergistic research
activities addressing the organisation and function of SAPKs
signalling with molecular genetics, proteomics, signalosome-analysis,
and molecular pharmacology including pharmacokinetics. Ultimately
STRESSPROTECT will have identified EXC-related SAPK signalosomes and
delivered novel inhibitor peptides against SAPK signalling underlying
EXC-mediated degeneration. STRESSPROTECT will
- (a) identify proteins in upstream regulatory complexes induced by EXC,
- (b) reveal the downstream targets mediating EXC and
- (c) elucidate specific protein-protein interaction sequences as targets for functional inhibition of SAPK signalling
- (d) extend the neuroprotective value of existing inhibitory peptides,
- (e) develop novel TAT-fused peptides inhibiting particular loci in the stress kinase pathways,
- (f) devise ways of targeting peptides specifically into EXC-affected cells and
- (g) carefully define the risk-benefit ratio prior to implementation in clinical trials.
We will be present at the FENS 2008 forum meeting with a Stressprotect satellite symposium.
For further information visit our members & research page.
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