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Content archived on 2024-05-29

Inhibition of stress activated protein kinase signalling as a therapeutic strategy against excitotoxicity

Objective

Excitotoxicity (EXC), neuronal death from excessive stimulation, contributes to a plethora of neurodegenerative conditions including cerebral ischemia and seizure-induced death. Stress activated protein kinases (SAPKs) of the JNK and p38 families have been identified as novel mediators of EXC death which is mainly executed by existing proteins demanding post-translational modifications. STRESSPROTECT members 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 window, (b) analysed the individual apoptotic actions of SAPK isoforms, and (c) provided important insights into signalling from glutamate-receptors. STRESSPROTECT gathers the European elite for SAPK signalling in the brain and for neuroprotection against EXC by pharmacological intervention in these pathways, and proposes a novel therapeutic concept 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. At the end STRESSPROTECT has identified EXC-related SAPK signalosomes and delivered novel inhibitor peptides against SAPK sig-nalling underlying EXC-mediated degeneration. STRESSPROTECT will identify (a) proteins in upstream regulatory complexes induced by EXC, (b) the downstream targets mediating EXC and (c) specific protein-protein interaction sequences as targets for functional inhibition of SAPK signalling; STRESSPROTECT (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 defines the risk-benefit ratio prospective to implementation in clinical trials.

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Keywords

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Topic(s)

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Call for proposal

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FP6-2003-LIFESCIHEALTH-I
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Funding Scheme

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STREP - Specific Targeted Research Project

Coordinator

UNIVERSITAETSKLINIKUM SCHLESWIG-HOLSTEIN, CAMPUS KIEL
EU contribution
No data
Total cost

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No data

Participants (7)

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