Objective 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. Fields of science 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 Topic(s) ERC-ADG-2014 - ERC Advanced Grant Call for proposal ERC-2014-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Host institution UNIVERSITE LIBRE DE BRUXELLES Net EU contribution € 2 250 000,00 Address AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel Belgium See on map Region Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 250 000,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITE LIBRE DE BRUXELLES Belgium Net EU contribution € 2 250 000,00 Address AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel See on map Region Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 250 000,00
