Project description DEENESFRITPL Evolutionary genetics assist protection against kidney disease Chronic kidney disease often manifests with loss of protein into the urine (proteinuria), an indication of proximal tubule and protein reabsorption dysfunction. The EU-funded RENOPROTECT project is working under the hypothesis that the albumin uptake receptor cubilin plays a key role in kidney homeostasis and in the protection against proteinuric kidney disease. Scientists will test the protective impact of common variants of the cubilin gene (CUBN) in pre-clinical models of renal disease and investigate their role in proximal tubule fitness and tissue repair. The project's results will provide important insight into kidney homeostasis and contribute towards the better diagnosis, prognosis and treatment of proteinuric kidney disease. Show the project objective Hide the project objective Objective Many forms of chronic kidney disease are featured by the loss of protein into the urine (proteinuria). When the cause of proteinuria lies within the glomerulus, such as in diabetic kidney disease, then the protein overload in the tubular lumen may lead to damage of the downstream tubular cells. Particularly vulnerable are proximal tubular cells (PTCs), because these cells are specialized in protein reabsorption and have a high metabolic demand. Dysfunction of the main albumin uptake receptor cubilin (encoded by the CUBN gene) leads to the reduction of albumin uptake and albuminuria. Here, we hypothesize that genetic variants in CUBN are key for providing a cell-to-cell variability that is beneficial for PTC homeostasis and resistance against proteinuric kidney disease. This hypothesis is based on our recent findings that 1.) CUBN mutations are well tolerated by humans despite their proteinuric effects and that 2.) the CUBN locus shows signatures of balancing selection during human evolution. To address this hypothesis, we will first functionally validate common CUBN variants and haplotypes in a humanized Drosophila model and test whether they provide protection against renal disease in mice. Second, we will explore monoallelic CUBN expression and partial cryptic exon inclusion as two possible genetic mechanisms by which CUBN variants could promote proximal tubule fitness and tissue repair. Finally, taking advantage of cubilin dysfunction as a “safe” means to avoid PTC overload, we will target PTC protein uptake in proteinuric mice with the help of a nanoparticle delivery method. Altogether, our integrative translational approach will combine human genetics and experimental studies to explore a new mechanism of proximal tubule homeostasis that may also be applicable to other tissues. Based on evolutionary genetics, we aim to establish a novel paradigm for kidney protection with high relevance for the diagnosis, prognosis and treatment of proteinuric kidney disease. Fields of science medical and health sciencesclinical medicineendocrinologydiabetesdiabetic nephropathynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicinemedical geneticsmedical and health sciencesbasic medicinephysiologyhomeostasismedical and health sciencesclinical medicinenephrologykidney diseases Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-COG - ERC Consolidator Grant Call for proposal ERC-2019-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution UNIVERSITATSKLINIKUM HEIDELBERG Net EU contribution € 1 945 250,00 Address IM NEUENHEIMER FELD 672 69120 Heidelberg Germany See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis 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 € 1 945 250,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITATSKLINIKUM HEIDELBERG Germany Net EU contribution € 1 945 250,00 Address IM NEUENHEIMER FELD 672 69120 Heidelberg See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis 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 € 1 945 250,00
