Objectif 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. Champ scientifique medical and health sciencesclinical medicinepsychiatrysleep disordersnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologymedical and health sciencesbasic medicinepathologymedical and health sciencesclinical medicinenephrologykidney diseases Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-ADG-2014 - ERC Advanced Grant Appel à propositions ERC-2014-ADG Voir d’autres projets de cet appel Régime de financement ERC-ADG - Advanced Grant Institution d’accueil UNIVERSITE LIBRE DE BRUXELLES Contribution nette de l'UE € 2 250 000,00 Adresse AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel Belgique Voir sur la carte Région Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 250 000,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire UNIVERSITE LIBRE DE BRUXELLES Belgique Contribution nette de l'UE € 2 250 000,00 Adresse AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel Voir sur la carte Région Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 250 000,00