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Quantitative functional assessment of gene therapeutics for Muscular Dystrophy

Objectif

Dystrophin is a large cytoskeletal protein that makes a bridge between the cytoskeletal actin microfilaments in muscle cells and the extracellular matrix, through the Dystrophin-Dystroglycan complex located at the plasma membrane. This strong link is responsible for conferring resistance to muscle contraction. Duchenne Muscular Dystrophy (DMD) is an X-chromosome linked disease caused by a mutation on the Dystrophin gene that results in damage to muscle fibers. Affected individuals rarely live beyond the third decade of life. Gene therapy is being trialed to replace the mutant protein. Since Dystrophin is a large protein, proposed gene therapies employ truncated versions of Dystrophin. Therapy faces delays because of poor understanding of the protein stability and levels required for functional recovery in the in vivo context. This proposed project aims to explore how Dystrophin stability and turnover is modulated by its structural domains, taking advantage of cutting edge in vivo imaging techniques applied to the zebrafish model. Several truncated Dystrophin constructs, containing different combinations of specific rod regions, are used on trials. The hypothesis that these differ in their ability to replace natural Dystrophin will be tested. By imaging Dystrophin-GFP fusions after genetic manipulation of single cells in the live animal, we will determine Dystrophin dynamics and function in the living organism at the single cell level, leading to insights into cytoskeletal biology. We will test the ability of truncated human Dystrophins to rescue zebrafish dystrophin mutants and determine how much, and when, Dystrophin is required to rescue muscle structure and function. Our proposal strongly promotes transfer of knowledge between developmental biology and applied clinical research. The project will establish the applicant as a key member of a multidisciplinary international team aiming to develop time- and cost-effective initial screens for gene therapeutics.

Champ scientifique (EuroSciVoc)

Programme(s)

Thème(s)

Appel à propositions

FP7-PEOPLE-2009-IEF
Voir d’autres projets de cet appel

Régime de financement

MC-IEF - Intra-European Fellowships (IEF)

Coordinateur

KING'S COLLEGE LONDON
Contribution de l’UE
€ 232 427,20
Adresse
STRAND
WC2R 2LS London
Royaume-Uni
Région
London Inner London — West Westminster
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
Aucune donnée