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

Descrizione del progetto

Approfondimento della rete capillare cerebrale

I capillari forniscono ossigeno e sostanze nutritive al cervello e contribuiscono a mantenere uno sviluppo sano e l’omeostasi. Tuttavia, il modo in cui questi minuscoli vasi si organizzano in una rete funzionale dopo la nascita rimane poco conosciuto. L’ipotesi di lavoro del progetto AngioArchitects, finanziato dal CER, è che le cellule della punta endoteliale, note per la formazione di nuovi germogli vascolari, agiscano da guida durante la crescita dei capillari. Essi propongono che queste cellule segnalino istruzioni alle microglia, le cellule immunitarie residenti nel cervello. I ricercatori utilizzeranno un approccio multidisciplinare per generare la prima visione dettagliata delle interazioni vascolari-immunitarie nel cervello in via di sviluppo. I risultati del progetto potrebbero avere potenziali implicazioni per le cure neonatali e le terapie cerebrovascolari.

Obiettivo

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.