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Investigating the crosstalk between Notch and YAP/TAZ in sprouting angiogenesis

Descripción del proyecto

La diafonía molecular durante la angiogénesis

La angiogénesis es un proceso fisiológico por el que se forman nuevos vasos sanguíneos a partir de la vasculatura existente. Comienza en el útero y se produce a lo largo de la vida normal, pero también es importante en el mantenimiento de las enfermedades, por ejemplo, en la progresión del cáncer. El equipo del proyecto financiado con fondos europeos Angio-NYT trabaja con la hipótesis de que la delimitación de las vías moleculares que regulan la angiogénesis conducirá a nuevos tratamientos antiangiogénicos. Los investigadores tienen por objeto estudiar y predecir el resultado de las perturbaciones moleculares en la angiogénesis combinando modelos experimentales y computacionales. Estos modelos ayudarán a identificar a los agentes de las vías de señalización clave y a allanar el camino hacia nuevos tratamientos.

Objetivo

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.

Coordinador

TECHNISCHE UNIVERSITEIT EINDHOVEN
Aportación neta de la UEn
€ 170 419,20
Dirección
GROENE LOPER 3
5612 AE Eindhoven
Países Bajos

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Región
Zuid-Nederland Noord-Brabant Zuidoost-Noord-Brabant
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 170 419,20

Socios (1)