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Dysfunction of the Blood-Brain Barrier in schizophrenia: molecular underpinnings of vulnerability or resilience (B3phrenia)

Schizophrenia (SZ) is a sexually dimorphic neurodevelopmental disorder that involves both genetic predisposition and early- and later-life environmental risk factors (e.g., maternal immune activation (MIA) by prenatal infection and cannabis use) that are associated with increased risks for SZ. However, the underlying mechanisms remain to be elucidated. The aim of B3phrenia project is to explore the link between blood-brain barrier (BBB) permeability and the vulnerability or resilience to SZ, identify sex-specific molecular changes and characterize the effect of risk factors such as MIA/cannabis on BBB integrity to understand the neurobiological basis of SZ. Combined in vivo and in vitro analyses of molecular alterations of BBB integrity using both animal models and induced pluripotent stem cells from patients with SZ will shed light on our understanding of the relationships between cannabis, sex, and BBB function and structure, and so enhance our knowledge about resilience and vulnerability to SZ. The interdisciplinary team of world-class translational researchers will employ state-ofthe-art techniques such as transcriptome and proteome profiles of peripheral blood mononuclear cells ‒ obtained from a unique clinical cohort of first-episode SZ patients‒ as well as state of the art BBB model systems to identify molecular pathways of BBB dysfunction and suitable sex-modulated targets with the aim of enhancing resilience and developing refined stratification of SZ patients.