Description du projet
Des chromosomes supplémentaires pourraient être liés à la réparation des reins
Le corps se développe et se répare constamment, alors que de nouvelles cellules se forment régulièrement grâce à la mitose. Durant la mitose, le matériel génétique est dupliqué et la cellule se divise en deux cellules filles qui reçoivent chacune une copie complète de chaque chromosome. L’endocycle est une variante normale du cycle cellulaire où les cellules répliquent leurs génomes sans se diviser. Bien qu’il soit répandu chez les protozoaires, les plantes et les animaux, son rôle dans la réparation des tissus des mammifères est obscur. ROAR examine le rôle potentiel des endocycles dans la récupération de la fonction rénale après une insuffisance rénale aiguë (IRA), et ces informations pourraient également contribuer à réduire la fréquence des insuffisances rénales chroniques survenant à la suite d’une IRA.
Objectif
Acute kidney injury (AKI) is a global public health concern which results in 1.7 million deaths per year. If not lethal in the acute phase, AKI is considered reversible as suggested by recovery of renal function. However, even mild AKI episodes carry substantial risk of developing subsequent chronic kidney disease (CKD). The pathophysiological basis for this phenomenon remains unclear.
Injury and death of tubular cells are recognized as the main factors in the pathogenesis of AKI and functional recovery from AKI was traditionally attributed to the regenerative capacity of tubular epithelial cells (TECs) which are believed to re-enter the cell cycle and repair the damage. Nevertheless, my preliminary data provide evidence that an endocycle-mediated response of remnant TECs may represent a critical mechanism of response to AKI.
Endocycles are cell cycle variants consisting of G and S phases alone that repeatedly proceed without cytokinesis and its role in repair of mammalian tissues is mostly unknown and totally unexplored in the kidney.
This proposal will be structured into 3 distinct objectives to address: 1. The physiologic relevance of endocycle for kidney function recovery after AKI 2. The role of endocycle in the progression of AKI to CKD; 3. The mechanism by which YAP1 drives endocycle and contributes to CKD development. To this end I will use lineage tracing techniques based on the FUCCI2aR reporter applied in different transgenic animal models of AKI, together with in vitro experiments in human primary cultures of renal tubular cells.
Collectively, the outcomes of this proposal are expected to provide an entirely novel view of the kidney’s response to AKI, to further our understanding of the processes that drive CKD following AKI, as well as to describe for the first time endocycle as a critical response mechanism to tissue injury in the mammalian kidney.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-RI - RI – Reintegration panelCoordinateur
50121 Florence
Italie