Cel 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. Dziedzina nauki medical and health sciencesclinical medicinepsychiatrysleep disordersnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologymedical and health sciencesbasic medicinepathologymedical and health sciencesclinical medicinenephrologykidney diseases Program(-y) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Temat(-y) ERC-ADG-2014 - ERC Advanced Grant Zaproszenie do składania wniosków ERC-2014-ADG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-ADG - Advanced Grant Instytucja przyjmująca UNIVERSITE LIBRE DE BRUXELLES Wkład UE netto € 2 250 000,00 Adres AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel Belgia Zobacz na mapie Region Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Rodzaj działalności Higher or Secondary Education Establishments Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 250 000,00 Beneficjenci (1) Sortuj alfabetycznie Sortuj według wkładu UE netto Rozwiń wszystko Zwiń wszystko UNIVERSITE LIBRE DE BRUXELLES Belgia Wkład UE netto € 2 250 000,00 Adres AVENUE FRANKLIN ROOSEVELT 50 1050 Bruxelles / Brussel Zobacz na mapie Region Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad Rodzaj działalności Higher or Secondary Education Establishments Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 250 000,00
