Descripción del proyecto
El papel del género en la homeostasis renal y las nefropatías
En comparación con los hombres, las mujeres parecen estar protegidas ante las nefropatías, incluido el cáncer de riñón. Este dimorfismo sexual ofrece a las mujeres una ventaja frente al deterioro de la función renal relacionada con la edad, que es la principal causa de las nefropatías. El equipo del proyecto SIMPOSION, financiado con fondos europeos, trabaja sobre la hipótesis de que la señalización de los estrógenos en los progenitores renales favorece su supervivencia y autorrenovación. Los investigadores también analizarán los fundamentos que indican que la mayor incidencia del cáncer de riñón en los varones puede explicarse por un menor número de progenitores renales y una mayor tasa de proliferación. Además, este eje progenitor renal de hormonas sexuales se estudiará bajo el prisma del embarazo.
Objetivo
Kidney disorders represent a major global health burden with a significant sexual dimorphism that is largely unexplained. My group first identified the stem cells of the kidney (renal progenitors) and demonstrated their crucial role in kidney disease.
Here, I propose that sex hormones regulate number and function of renal progenitors to empower females to face the hemodynamic and metabolic challenges of pregnancy. I further propose that this process impacts on sexual dimorphisms in incidence and outcome of kidney diseases including kidney cancer. A multitude of unpublished data obtained with primary human progenitor cultures and unique mouse models of progenitor-specific sex hormones receptor knockout already support my concepts. I will demonstrate that, starting from the age of fertility, estrogen signaling in renal progenitors supports their survival and self-renewal, which is needed to increase their capacity to generate new podocytes and tubular epithelial cells. I will show that failure to produce a sufficient number of podocytes from estrogen-activated renal progenitors promotes preeclampsia and fetal growth retardation. This is a completely new pathophysiological concept of why women with a mismatch of nephron number and pregnancy-related hyperfiltration develop preeclampsia. I will further demonstrate that the same mechanism protects fertile women from severe forms of glomerular injury unrelated to pregnancy. Finally, I will prove that to compensate for the lower number of renal progenitors, testosterone pushes them to proliferate more in males and that this can explain the increased incidence of most prevalent forms of kidney cancer, that derive from renal progenitors. This topic is a direct continuation of my previous studies on renal progenitors supported by ERC Starting and Consolidator grants and will unravel fundamental paradigms in kidney physiology, adaptation, and disease with important implications for prevention and management of kidney disease.
Ámbito científico
- medical and health sciencesclinical medicineobstetricsfetal medicine
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicinephysiology
- medical and health sciencesclinical medicinenephrologykidney diseases
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
50121 Florence
Italia