Descrizione del progetto
I cromosomi extra potrebbero essere collegati alla riparazione renale
Il nostro corpo è continuamente sottoposto a processi di crescita e riparazione, con nuove cellule che si formano su base regolare attraverso la mitosi. Durante la mitosi, il materiale genetico viene duplicato e la cellula si divide ottenendo due cellule figlie, ognuna delle quali riceve una copia completa di ogni cromosoma. L’endociclo è una variante normale del ciclo cellulare in cui le cellule replicano i propri genomi senza dividersi. Diffuso nei protozoi, nelle piante e negli animali, il suo ruolo nella riparazione dei tessuti dei mammiferi non è chiaro. ROAR sta esplorando il ruolo potenziale degli endocicli nel recupero della funzionalità renale dopo una lesione renale acuta. La comprensione potrebbe anche aiutare a ridurre l’insorgenza di malattie renali croniche a seguito del recupero da un danno renale acuto.
Obiettivo
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.
Campo scientifico
Programma(i)
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Meccanismo di finanziamento
MSCA-IF-EF-RI - RI – Reintegration panelCoordinatore
50121 Florence
Italia