Objetivo
Plasmodium falciparum, the protozoan parasite responsible for the lethal form of human malaria, causes between 1 and 3 million deaths every year. Within erythrocytes, the malarial parasite is surrounded by a vacuole as a consequence; it is separated from t he extracellular environment by three different membranes. The intracellular survival of the parasite requires a bidirectional vesicular transport system, regulated by Rab GTPases. The aim of this project is to determine whether vesicular transport is regulated in parasites by phosphorylation of Rab GTPases by protein kinases.
This application is based in the post-genomic era, where the identification of novel drug targets is facilitated by the availability of parasite genome databases. It is functional genomics and combines genetics with cellular biology and biochemistry. Preliminary experiments have established that P. falciparum Rab11B can be phosphorylated in vitro by the P. falciparum PfPK7. We intend to extend this study to the 10 other parasite Rabs using the 13 protein kinases for which we have active recombinant enzymes.
The identification of the regulation network of this bidirectional vesicular transport is essential to understand the development of the parasite. Once we have determined which R abs are substrates for a given kinase we will confirm the interacting complex in vivo by combining Pull-Down experiments and Mass Spectrometry studies. Mass Spectrometry will also be used to identify the phosphorylated residues in each Rab and the site will be altered by mutagenesis.
The impact of phosphorylation on Rab-mediated vesicular transport will be assessed by knocking-in mutated P. berghei genes coding for phosphorylation-resistant Rab GTPases. Demonstration that phosphorylation can regulate bidirectional vesicular transport within infected erythrocytes will render these novel Rab-kinases ideal targets for the development of new anti-malarial drugs.
Ámbito científico (EuroSciVoc)
CORDIS clasifica los proyectos con EuroSciVoc, una taxonomía plurilingüe de ámbitos científicos, mediante un proceso semiautomático basado en técnicas de procesamiento del lenguaje natural.
CORDIS clasifica los proyectos con EuroSciVoc, una taxonomía plurilingüe de ámbitos científicos, mediante un proceso semiautomático basado en técnicas de procesamiento del lenguaje natural.
- ciencias médicas y de la saludciencias de la saludenfermedad infecciosamalaria
- ciencias naturalesinformática y ciencias de la informaciónbase de datos
- ciencias naturalesciencias químicasquímica analíticaespectrometría de masas
- ciencias naturalesciencias biológicasgenéticagenoma
- ciencias naturalesciencias biológicasbioquímicabiomoléculasproteínasenzima
Para utilizar esta función, debe iniciar sesión o registrarse
Palabras clave
Convocatoria de propuestas
FP6-2004-MOBILITY-11
Consulte otros proyectos de esta convocatoria
Régimen de financiación
ERG - Marie Curie actions-European Re-integration GrantsCoordinador
Francia