Brain arteriovenous malformations (bAVMs) are high-flow vascular anomalies characterised by direct connections between arteries and veins, bypassing the capillary network. They are a significant cause of intracranial hemorrhagic stroke, especially in young populations. Despite advances in vascular biology, the underlying mechanisms of bAVMs remain poorly understood, and specific therapeutic interventions are lacking. Recent studies implicate somatic activating mutations in KRAS and downstream MAPK-ERK signalling in bAVMs pathogenesis, with endothelial cells (ECs) playing a central role in these processes. KRAS mutation drives EC proliferation, angiogenesis, and endothelial-mesenchymal transition (EndMT), critical factors in bAVM progression. Interestingly, the host laboratory recently identified SHANK3 as an essential inhibitor of active and mutant KRAS signalling. SHANK3, a scaffolding protein initially recognised for its role in neurons, influences cell adhesion and migration through pathways linked to KRAS. SHANK3´s regulatory roles in maintaining the blood-brain barrier (BBB) integrity and interaction with KRAS have not been explored in the context of bAVMs. Based on compelling preliminary data, this researcher hypothesises that SHANK3-KRAS interactions represent a novel therapeutic axis for treating bAVMs through modulation of endothelial signalling pathways.

This study focuses on three key aims: (1) to elucidate KRAS-driven endothelial pathogenesis in bAVMs by characterising the impact of specific KRAS mutations (e.g. G12V, G12D) on EC behaviour; (2) to investigate SHANK3´s role in ECs, including its influence on KRAS-MAPK signalling and BBB integrity; and (3) to develop innovative therapeutic strategies targeting SHANK3 -KRAS interaction.

State-of-the-art methodologies, including CRISPR/Cas9 genome editing, proximity-dependent biotinylation (PDB), advanced endothelial assays, and genetically engineered mouse models, will be utilised. Therapeutic interventions using SHANK3-targeting as a therapeutic strategy. The anticipated findings will not only fill critical knowledge gaps but also pave the way for clinical translation, offering hope for bAVM patients through precision-based therapies.