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

Project description

Molecular crosstalk during angiogenesis

Angiogenesis is a physiological process whereby new blood vessels form from the existing vasculature. It begins in utero and occurs throughout normal life, but it is also important in disease maintenance, for example in the progression of cancer. The working hypothesis of the EU-funded Angio-NYT project is that delineation of the molecular pathways that regulate angiogenesis will lead to novel anti-angiogenic therapies. Researchers aim to study and predict the outcome of molecular perturbations in angiogenesis by combining experimental and computational models. These will help identify the players in key signalling pathways and pave the way for new treatments.

Objective

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.

Coordinator

TECHNISCHE UNIVERSITEIT EINDHOVEN
Net EU contribution
€ 170 419,20
Address
GROENE LOPER 3
5612 AE Eindhoven
Netherlands

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Region
Zuid-Nederland Noord-Brabant Zuidoost-Noord-Brabant
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 170 419,20

Partners (1)