Descrizione del progetto
La genetica evolutiva agevola la protezione contro la malattia renale
La malattia renale cronica si manifesta spesso con la perdita di proteine nell’urina (proteinuria), un indicatore della disfunzione del tubulo prossimale e del riassorbimento delle proteine. Il progetto RENOPROTECT, finanziato dall’UE, sta lavorando sull’ipotesi che la cubilina, il recettore di assorbimento dell’albumina, svolga un ruolo chiave nell’omeostasi renale e nella protezione contro le malattie renali proteinuriche. Gli scienziati testeranno l’impatto protettivo delle varianti comuni del gene cubilina (CUBN) in modelli pre-clinici della malattia renale ed esamineranno il loro ruolo nell’adattamento ai tubuli prossimali e nella riparazione tissutale. I risultati del progetto forniranno importanti informazioni sull’omeostasi renale e contribuiranno a diagnosi, prognosi e trattamento migliori della malattia renale proteinurica.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
69120 Heidelberg
Germania