Description du projet
Le rôle du genre dans la maladie et l’homéostasie des reins
Par rapport aux hommes, les femmes semblent être plus protégées contre les maladies rénales, y compris le cancer du rein. Ce dimorphisme sexuel accorde aux femmes un avantage face au déclin lié à l’âge de la fonction rénale, qui s’avère être la cause principale des maladies rénales. Le projet SIMPOSION, financé par l’UE, part de l’hypothèse que la signalisation des œstrogènes dans les progéniteurs rénaux favorise leur survie et leur autorenouvellement. Les chercheurs vérifieront également l’hypothèse selon laquelle l’incidence supérieure de cancer du rein chez les hommes peut être expliquée par un nombre inférieur de progéniteurs rénaux et un taux plus élevé de prolifération. En outre, cet axe hormones sexuelles-progéniteurs rénaux sera étudié dans le cadre de la grossesse.
Objectif
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 A multitude of unpublished data obtained with primary human progenitor cultures and unique mouse models of progenitor-specific sex hormones receptor knockout already support my concepts.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.
Champ scientifique
- 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
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
50121 Florence
Italie