Endothelial-microglial communication as a sculptor of brain capillary network architecture

Description du projet

Aperçu du réseau capillaire cérébral

Les capillaires fournissent de l’oxygène et des nutriments au cerveau et contribuent au maintien d’un développement sain et de l’homéostasie. Cependant, la manière dont ces minuscules vaisseaux s’organisent en un réseau fonctionnel après la naissance reste mal comprise. L’hypothèse de travail du projet AngioArchitects, financé par le CER, est que les cellules endothéliales de pointe, connues pour former de nouveaux bourgeons vasculaires, agissent comme des guides pendant la croissance capillaire. Les chercheurs proposent que ces cellules transmettent des instructions aux microglies, les cellules immunitaires résidentes du cerveau. Ils adopteront une approche pluridisciplinaire afin de générer la première vue détaillée des interactions vasculaires-immunitaires dans le cerveau en développement. Les résultats du projet pourraient avoir des implications potentielles pour les soins néonatals et les thérapies cérébrovasculaires.

Objectif

Brain capillaries are the lifelines of the brain, supplying essential nutrients and oxygen and safeguarding its delicate environment. Therefore, proper establishment of this hierarchically branched circuitry is crucial for brain growth and function throughout life. Orchestrating the creation of a functional vascular network requires coordinated signalling among endothelial cells, the vessels´ building blocks, with adjacent cells. Despite its importance, the exact spatiotemporal events, and molecular bases of the capillary network construction during postnatal development remain a mystery. Elucidating this dynamic process within the intact developing mammalian brain in both space and time is a challenging but a necessary step to unveil this fascinating biological knowledge gap. Towards this goal, I recently established a longitudinal live imaging approach to capture brain development processes with minimal perturbation. Based on preliminary work, I postulate that endothelial tip cells instruct microglia, the brain resident immune cells, to serve as pathfinders and guide them to their target vessel. To address this original and innovative hypothesis, ANGIOARCHITECTS proposes to employ a powerful multi-disciplinary combination of mouse genetics, two-photon live imaging, omics profiling, high-resolution microscopy mapping, and computational modelling tools to reveal the developmental principles of building the capillary network, focusing on communications between endothelial tip cells and microglia. This pioneering project will be the first to offer unprecedented imaging of vascular-immune interactions during angioarchitecture formation in the neonatal period, when the brain is highly susceptible to insults and injuries. ANGIOARCHITECTS will not only advance the frontiers of vascular research but also holds immense potential for driving future investigations in neonatal healthcare and clinical therapies targeting cerebrovascular disorders.