Description du projet
Utiliser des organoïdes rénaux dans la recherche de nouvelles thérapies de néphropathie diabétique
La néphropathie constitue une morbidité majeure du diabète qui évolue souvent vers une maladie rénale terminale, car il n’existe aucun traitement en dehors des stratégies de contrôle glycémique et de la pression artérielle. Pour résoudre ce problème, le projet EPIORGABOLISM, financé par l’UE, travaille sur un nouveau modèle de néphropathie diabétique qui pourrait contribuer aux futurs efforts de découverte de médicaments. Les chercheurs utiliseront des cellules souches embryonnaires humaines pour dériver des organoïdes rénaux et étudieront comment les altérations métaboliques du diabète peuvent reprogrammer épigénétiquement les cellules rénales et provoquer une fibrose. Les résultats fourniront des informations importantes sur la pathologie et la progression de la maladie et contribueront à identifier de nouvelles cibles thérapeutiques.
Objectif
Diabetic Nephropathy is the leading cause of end-stage renal disease (ESRD). To date, treatment of DN is mainly based on drugs acting on glycaemic and blood pressure control, as there is no validated therapy able to stop the progression towards renal failure. One of the main impediments for developing new therapies for DN has been the lack of a good preclinical model which can recapitulate important functional, structural, and molecular features of advanced human diabetic kidney disease. Here, we aim to develop a DN modelling using human Embryonic Stem Cell (hESC) derived kidney organoids which can recapitulate the in vivo architecture, functionality, and genetic signature of DN. Due to the increasing evidences that links aberrant DNA methylation with kidney fibrosis and metabolic reprograming in DN, we hypothesize that early DN progression is promoted by the metabolic alterations occurring in diabetic patients, resulting in the epigenetic reprogramming of kidney proximal tubular epithelial cells (KPTCs). Based in my background in the fields of metabolism and diabetes, together with the expertise of Dr. Montserrat in the field of somatic reprograming, DN and tissue regeneration/differentiation, this proposal seeks to:1) Elucidate the methylation status of the promoters/enhancers of genes encoding enzymes and regulators of fibrosis and fatty acid oxidation in proximal tubular cells obtained from diabetic patients at different stages of DN progression 2) Establish two in vitro models using hESC-derived kidney organoids; an engineered DN in vitro model, using CRISPR Cas9 to mimic the epigenome signature of DN patients and a physiological DN in vitro model which mimic the diabetic physiological chemistry. The information gained from this DN modelling will offer improved insight into disease pathology and progression. Moreover, it may also serve as a tool for drug discovery to identify therapeutic targets for DN.
Champ scientifique
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesclinical medicineendocrinologydiabetesdiabetic nephropathy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesbasic medicinepathology
- medical and health sciencesclinical medicinenephrologykidney diseases
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
08028 Barcelona
Espagne