Descripción del proyecto
Unos cromosomas adicionales podrían estar relacionados con la reparación renal
El cuerpo está continuamente sometido a procesos de crecimiento y reparación, ya que regularmente se forman nuevas células a través de la mitosis. Durante este proceso, el material genético se duplica y la célula se divide en dos células hijas que reciben una copia completa de cada cromosoma. El endociclo es una variante normal del ciclo celular en el que las células replican sus genomas sin dividirse. Generalizado en los protozoos, las plantas y los animales, no está clara su función en la reparación de los tejidos de los mamíferos. ROAR está estudiando la posible función de los endociclos en la recuperación de la función renal tras una lesión renal aguda. Esta nueva percepción también podría ayudar a reducir la aparición de enfermedades renales crónicas tras la recuperación de una lesión renal aguda.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-RI - RI – Reintegration panelCoordinador
50121 Florence
Italia