Aging and decline of renal progenitor regenerative capacity: identification of molecular mechanisms and anti-senescent molecules as therapeutic treatments for CKD
During the aging process, the kidney experiences progressive functional decline as well as macroscopic and microscopic histological alterations, which are accentuated by systemic comorbidities like hypertension and diabetes mellitus, or by preexisting or underlying kidney diseases. Indeed, progressive aging of the population is accompanied by an increase in the prevalence of chronic kidney disease (CKD) worldwide. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Therefore, we hypothesized that senescence could also affect the regenerative capacity of adult renal progenitor cells (RPCs), reducing kidney repair and increasing the risk of kidney dysfunctions.
To date a method to reduce renal stem/progenitor cell senescence is missing, which it may be extremely important to support the kidney regenerative capacity. In this project, we will identify the role of RPCs during aging by taking advantage of transgenic mouse models, which specifically track them in the kidney. In particular, we will investigate the decline of the regenerative capacity of RPCs and their senescence during physiologic aging in mice.
Moreover, we will investigate the molecular mechanisms involved in the decline of regenerative capacity and triggering RPC senescence, by using scRNA-sequencing approach and by integrating the transcriptomic profile of RPCs with that obtained by DNA methylation analysis. In addition, we will study and generate the RPC DNA methylation clock in mice, getting increasingly accurate in predicting the individual biological age. Collectively, this acquired knowledge may lead to identification of potential therapeutic targets. We, then, will identify anti-aging molecules to slow down the RPC senescence and CKD progression by drug and natural compound screening with two high content library and we will validate found molecules in a Pax2/Confetti senescence mice model. Overall, this proposal aims to identify RPCs as a potential target to slow down the kidney aging and its detrimental consequences.
Data di avvio 30 Novembre 2023
Data di completamento 30 Novembre 2025
Total cost € 119794
Progetto P2022W5N2X_02 finanziato all’interno del Bando PRIN 2022 PNRR di cui al Decreto Direttoriale n. 1409 del 14/9/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23024830001
Ultimo aggiornamento
04.06.2024