Objectif Until recently, the majority of motor neuron disease (MND) research has used cellular and animal models of disease based on the over-expression of mutant superoxide dismutase (SOD1). SOD1 mutations cause protein aggregation and toxicity but are found in only 5% of all MND patients. In contrast, aggregates of the TAR DNA binding protein (TDP-43), have recently been identified in motor neurons and glia in greater than 90% of MND patients, and in cortical neurons in 60% of fronto-temporal lobar dementia (FTLD-U) patients. The Shaw Lab has recently identified TDP-43 mutations in rare familial and sporadic MND patients and confirmed a role for TDP-43 aggregation in neurodegeneration. Interestingly, TDP-43 aggregates are absent in both patients and transgenic mice with SOD1 mutations, suggesting that the mechanism of SOD1-mediated degeneration is distinct from that occurring in the vast majority of MND patients. This may explain why drugs which modify disease in SOD1 mutant mice have not been effective in clinical trials in MND patients. The identification of compounds which can reduce TDP-43 aggregation is likely to have broader therapeutic potential for MND and FTLD-U than those which modulate SOD1. We will develop a range of wildtype and mutant TDP-43 over-expressing cell lines in order to recapitulate disease-specific aggregation and/or toxicity. We will then use high throughput image-based screening to investigate the National Institute of Neurological Disorders and Stroke (NINDS) library of 1040 Federal Drug Authority approved compounds for their ability to reduce the aggregation and/or toxicity of mutant TDP-43. ‘Hit’ compounds will be validated in the context of motor neurons differentiated from induced pluripotent stem cells (iPSCs). These iPSCs will be derived from MND patient skin fibroblasts. By identifying pathways common to drugs which modulate disease in this powerful human MND motor neuron system, we hope to determine the key therapeutic targets in MND. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesbasic medicineneurologydementianatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicineneurologystroke Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2009-IIF - Marie Curie Action: "International Incoming Fellowships" Appel à propositions FP7-PEOPLE-2009-IIF Voir d’autres projets de cet appel Régime de financement MC-IIF - International Incoming Fellowships (IIF) Coordinateur KING'S COLLEGE LONDON Contribution de l’UE € 174 240,80 Adresse STRAND WC2R 2LS London Royaume-Uni Voir sur la carte Région London Inner London — West Westminster Type d’activité Higher or Secondary Education Establishments Contact administratif Paul Labbett (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée