Obiettivo
Aspergillus fumigatus is the most important air-borne fungal pathogen, causing severe infections with invasive growth in immunocompromised patients. For growth in all habitats, the fungus needs to be able to sense environmental stimuli and to transduce signals via specific signalling cascades. Calmodulin/calcineurin, Ras/cAMP, mTOR and general Mitogen-activated protein kinase (MAPK) signalling pathways are involved in the regulation of various cellular responses in eukaryotes. Previous studies revealed that the central core of the MAPK cell wall integrity signalling pathway in A. fumigatus is composed of three protein kinases. Deletion of these genes resulted in severe sensitivity of the mutants against cell wall-disturbing compounds and drastic alterations of the fungal morphology. Nevertheless, the mutants were still virulent in a murine infection model. Even more, therapeutic treatment with medical commercial cell wall-acting compounds, like echinocandins and azoles, did not result in effective treatment against aspergillosis, indicating the importance of cell wall assembling pathways compensating the inhibition caused by cell wall-disturbing compounds. Protein kinase activation requires phosphorylation. This process is reversible even in the continued presence of activating stimuli. The importance of protein phosphatases for signalling pathways and cross talk interactions is emerging. Ontology classification analysis revealed that the A. fumigatus genome contains 24 genes coding for putative protein phosphatases. A comprehensive and extensive study on protein phosphatases in filamentous fungi has never been attempted so far. Here, we propose to study protein phosphatase families in A. fumigatus. Mutant strains will be used to investigate cell wall compensatory pathways in order to identify new molecules for therapeutic intervention against aspergillosis.
Campo scientifico
Invito a presentare proposte
FP7-PEOPLE-2009-RG
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Meccanismo di finanziamento
MC-ERG - European Re-integration Grants (ERG)Coordinatore
07745 Jena
Germania