Obiettivo Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identificationof the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similaritieswith proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced underinflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRAprotein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infecthumans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization andtherefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease.Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublishedresults also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viralstimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on thecontrol of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection.This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan ofactivated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and(ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail thephysiological function of APOLs by studying the phenotype of transgenic mice either expressing humanAPOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, wepropose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produceSRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that inpodocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening newperspectives to treat kidney disease. Campo scientifico medical and health sciencesclinical medicinepsychiatrysleep disordersnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologymedical and health sciencesbasic medicinepathologymedical and health sciencesclinical medicinenephrologykidney diseases Programma(i) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Argomento(i) ERC-ADG-2014 - ERC Advanced Grant Invito a presentare proposte ERC-2014-ADG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-ADG - Advanced Grant Istituzione ospitante UNIVERSITE LIBRE DE BRUXELLES Contribution nette de l'UE € 2 250 000,00 Indirizzo AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel Belgio Mostra sulla mappa Regione Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 250 000,00 Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto UNIVERSITE LIBRE DE BRUXELLES Belgio Contribution nette de l'UE € 2 250 000,00 Indirizzo AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel Mostra sulla mappa Regione Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 250 000,00