Projektbeschreibung
Molekularer Crosstalk bei der Angiogenese
Die Angiogenese ist ein physiologischer Vorgang, bei dem neue Blutgefäße aus dem vorhandenen Gefäßsystem gebildet werden. Er beginnt im Mutterleib und tritt das ganze Leben auf, spielt jedoch auch bei der Aufrechterhaltung von Krankheiten, beispielsweise beim Fortschreiten von Krebs, eine Rolle. Die Arbeitshypothese des EU-finanzierten Projekts Angio-NYT ist, dass eine Beschreibung der molekularen Pfade, die die Angiogenese regulieren, zu neuartigen anti-angiogenen Therapien führen wird. Die Forschenden wollen das Ergebnis molekularer Störungen bei der Angiogenese untersuchen und vorhersagen, indem sie experimentelle und computergestützte Modelle kombinieren. Dadurch werden sie die einzelnen Parteien bei wichtigen Signalwegen bestimmen und den Weg für neue Therapien ebnen.
Ziel
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.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
5612 AE Eindhoven
Niederlande