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CCM DISEASE FROM A REDOX PERSPECTIVE : KRIT1 ACTS AS A TRAFFIC WARDEN AT THE BUSY CROSSROADS BETWEEN REDOX SIGNALING AND CCM PATHOGENESIS

Mardi 28 mars 2023 11:00 - Duree : 1 heure
Lieu : Salle de Conférence de l’IAB - Rond Point de La Chantourne, 38700 La Tronche (arrêt de tram Grand Sablon, ligne B)

Orateur : Saverio Francesco RETTA (University of Torino, Italy)

Résumé :

Background : KRIT1 (Krev_interaction_trapped1) is a scaffolding protein that plays a critical role in vascular morphogenesis and homeostasis. Its loss-of-function has been unequivocally associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease of genetic origin characterized by defective endothelial cell-cell adhesion and ensuing structural alterations and hyperpermeability in brain capillaries. KRIT1 contributes to the maintenance of endothelial barrier function by stabilizing the integrity of adherens junctions and inhibiting the formation of actin stress fibers.

Knowledge Advances : Among multiple regulatory mechanisms proposed so far, significant evidence resulting from our original discoveries reported over the past decade has clearly shown that the role of KRIT1 in the stability of endothelial barriers, including the blood-brain barrier, is largely based on its involvement in the complex machinery governing cellular redox homeostasis and responses to oxidative stress and inflammation. KRIT1 loss-of-function has indeed been demonstrated to cause an impairment of redox-sensitive mechanisms involved in spatiotemporal regulation of cell adhesion and signaling, including major redox-sensitive transcriptional pathways and autophagy, which ultimately leads to decreased cell-cell junction stability and enhanced sensitivity to oxidative stress and inflammation.

Core Arguments : Overall, we will provide an overview of the role of KRIT1 and related CCM proteins in redox mechanisms that influence endothelial cell adhesion and barrier function, including growing evidence that supports a novel model wherein redox signaling forms the common link between the various pathogenetic mechanisms and therapeutic approaches hitherto associated with CCM disease.

Ongoing Directions : The in-depth characterization of KRIT1 role in redox control of endothelial barrier physiology and defense against oxy-inflammatory insults is providing valuable insights into a comprehensive understanding of CCM pathogenesis, the identification of genetic modifiers and prognostic/predictive biomarkers, and the development of precision medicine strategies, including emerging innovative nanotechnology-based approaches.

Contact : karin.sadoul@univ-grenoble-alpes.fr



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