Descripción del proyecto
Usar organoides de riñones en la búsqueda de nuevos tratamientos de la nefropatía diabética
La nefropatía es una morbilidad principal de la diabetes y suele evolucionar hasta la insuficiencia renal terminal, ya que no existen tratamientos aparte de las estrategias de control de glucemia y tensión arterial. Para abordar esta limitación, el proyecto financiado con fondos europeos EPIORGABOLISM está trabajando en un modelo novedoso de nefropatía diabética que podría ayudar en esfuerzos futuros para descubrir fármacos. Los investigadores utilizarán células madre embrionarias humanas para obtener organoides de riñones y estudiar la forma en que las alteraciones metabólicas pueden reprogramar epigenéticamente las células renales y causar fibrosis. Los resultados proporcionarán información importante sobre la patología y la progresión de la enfermedad y ayudarán a identificar nuevas dianas terapéuticas.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
08028 Barcelona
España