RENOPROTECT
Financiado
Targeting tubular reabsorption for kidney protection
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...
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.
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Duración del proyecto: 69 meses
Fecha Inicio: 2020-03-10
Fecha Fin: 2025-12-31
Fecha Fin: 2025-12-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2020-03-10
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2019-COG:
ERC Consolidator Grant
Cerrada
hace 5 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
UNIVERSITATSKLINIKUM HEIDELBERG
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
1.13M€ |
Participante