Projektbeschreibung
Evolutionsgenetik unterstützt Schutz vor Nierenerkrankungen
Chronische Nierenerkrankungen manifestieren sich häufig in Form von erhöhten Proteinausscheidungen im Urin (Proteinurie), die ein Hinweis auf eine Dysfunktion der proximalen Tubuli und der Proteinresorption sind. Das EU-finanzierte Projekt RENOPROTECT verfolgt die Hypothese, dass der Albumin-Aufnahmerezeptor Cubilin eine Schlüsselrolle bei der Nierenhomöostase und beim Schutz vor Nierenerkrankungen mit Proteinurie spielt. Das Team wird die schützende Wirkung von häufigen Varianten des Cubilin-Gens (CUBN) anhand präklinischer Modelle von Nierenkrankheiten testen und deren Rolle in Hinsicht auf die Fitness der proximalen Tubuli und die Gewebereparatur wissenschaftlich untersuchen. Die Ergebnisse des Projekts werden wichtige Einblicke in die Nierenhomöostase zulassen und zu einer besseren Diagnose, Prognose und Behandlung der Nierenerkrankung mit pathologischer Proteinurie beitragen.
Ziel
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.
Wissenschaftliches Gebiet
- medical and health sciencesclinical medicineendocrinologydiabetesdiabetic nephropathy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinemedical genetics
- medical and health sciencesbasic medicinephysiologyhomeostasis
- medical and health sciencesclinical medicinenephrologykidney diseases
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
69120 Heidelberg
Deutschland