Descrizione del progetto
Cross-talk molecolare durante l’angiogenesi
L’angiogenesi è un processo fisiologico mediante il quale si formano nuovi vasi sanguigni a partire dalla vascolarizzazione esistente. Inizia nell’utero e prosegue per tutta la vita normale, ma è importante anche nella perseveranza della malattia, ad esempio nella progressione del cancro. L’ipotesi di lavoro del progetto Angio-NYT, finanziato dall’UE, è che la delineazione delle vie molecolari che regolano l’angiogenesi porterà a nuove terapie anti-angiogeniche. I ricercatori mirano a studiare e prevedere l’esito delle perturbazioni molecolari nell’angiogenesi combinando modelli sperimentali e computazionali. Ciò contribuirà a identificare i protagonisti delle principali vie di segnalazione e ad aprire la strada a nuovi trattamenti.
Obiettivo
Our limited understanding of angiogenesis, the process leading to the formation of new blood vessels from pre-existing ones, hinders the design of new treatments for associated diseases such as cancer, ischemia, and diabetic retinopathy. It is well established that sprouting angiogenesis involves a process of endothelial cell phenotype selection mediated by the interaction between vascular endothelial growth factor (VEGF) and Notch signalling. Recently, it has been demonstrated that the Yes-associated protein (YAP) and the transcriptional coactivator with a PDZ-binding domain (TAZ), the main mediators of the Hippo signalling pathway, interact with VEGF and influence Notch signalling. However, it is still unclear how the effects of YAP/TAZ on Notch signalling contribute in regulating angiogenesis. In this project, I will adopt an approach combining experimental and computational techniques. First, I will culture endothelial cell monolayers on differently stiff substrates and I will perturb Notch via ligand-coated beads and YAP/TAZ activity via pharmacological inhibition. With the information deriving from these experiments, I will develop a unique agent-based computational model for angiogenesis, accounting for the interplay between Notch and YAP/TAZ. I will use this model to predict the effects of the Notch-YAP/TAZ crosstalk on angiogenesis. Finally, I will adapt previously established in vitro experimental systems recapitulating angiogenesis in three-dimensional environments. In these systems, I will vary the matrix stiffness, inhibit YAP/TAZ activation, perturb Notch signalling with ligand-coated beads, and measure the changes to parameters such as sprout and branch density and the dynamics of individual cell behaviour. This interplay between experimental and computational techniques will enhance our understanding of the crosstalk between Notch and Hippo-YAP/TAZ in regulating angiogenesis, with the potential to inspire new medical treatments.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
5612 AE Eindhoven
Paesi Bassi