Angio-NYT · Investigating the crosstalk between Notch and YAP/TAZ in sprouting angiogenesis
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-09-01 → 2022-08-31
- EU contribution
- €170,419
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Investigating the crosstalk between Notch and YAP/TAZ in sprouting angiogenesis
Angiogenesis is the process leading to the formation of new blood vessels from pre-existing ones. This phenomenon is crucial for health and diseases, such as cancer and ischemia. Regulation of angiogenesis is thus key for numerous medical treatments, but an optimal control still needs to be achieved. To this aim, a more complete understanding of the regulatory mechanisms is necessary. Notch is a cell-cell signalling that strongly regulates angiogenesis; Notch spatiotemporal dynamics influences the vascular network topology that results from angiogenesis. Identifying new spatiotemporal regulators of Notch dynamics might lead to the development of new strategies to control angiogenesis and, thus, new medical treatments. In this project, by combining experiments and simulations, I aimed to identify new techniques to spatiotemporally control angiogenesis, via Notch regulation. This was achieved by: (objective 1) experimentally characterizing Notch and its cross-talking signalling pathways; (objective 2) developing computational models of angiogenesis accounting for Notch with its cross-talking pathways; and (objective 3) validating the computational findings via experiments. In terms of professional development (PD), I aimed to: (PD aim I) train in cell experiments and computational modelling of angiogenesis; (PD aim II) establish new international collaborations; and (PD aim iii) obtain a faculty position at a European university.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- TECHNISCHE UNIVERSITEIT EINDHOVEN · EindhovenCoordinatorNetherlands
- THE TRUSTEES OF BOSTON UNIVERSITY · BOSTON MAUnited States
Links
Data: CORDIS, © European Union