Endothelial Hedgehog autocrine signaling at the Blood Brain Barrier controls inflammatory Central Nervous System lesion size and severity through Gas1 co-receptor modulation.

Description du projet

Signalisation croisée au niveau de la barrière hémato-encéphalique et contrôle de l’inflammation du système nerveux central

La barrière hémato-encéphalique (BHE) isole le parenchyme du système nerveux central (SNC) de la circulation périphérique. Cependant, dans le cas de la sclérose en plaques (SEP), les cellules inflammatoires et les protéines plasmatiques pénètrent dans le SNC et provoquent la formation de lésions en raison d’une perméabilité anormale de la BHE. Financé par le programme Actions Marie Sklodowska-Curie, le projet EFHHBBBMS vise à mieux comprendre la physiopathologie de la BHE, en particulier dans le cadre de la SEP. Des études antérieures ont impliqué la voie Hedgehog comme régulateur de l’intégrité de la BHE dans la sclérose en plaques, le VIH et les accidents vasculaires cérébraux. Le projet actuel testera l’hypothèse selon laquelle la signalisation induite par Desert Hedgehog dans les cellules endothéliales affecte l’expansion des lésions inflammatoires au niveau des jonctions intercellulaires de la BHE grâce à l’implication du corécepteur Gas1, ce qui représente une nouvelle cible potentielle pour des thérapies efficaces contre la sclérose en plaques.

Objectif

"Being at a major turning point in my career, after a rewarding postdoctoral fellowship in the United States, I’m applying to the MSCA-IF-2017 to ensure my return to Europe as an independent researcher in neurovascular biology. I built a proposal with the purpose of providing new understanding of Blood Brain Barrier (BBB) pathophysiology, particularly in the setting of Multiple Sclerosis. My hypothesis is that Desert Hedgehog-induced autocrine signaling in endothelial cells controls inflammatory lesion expansion via the regulation of intercellular junctions at the BBB through its co-receptor Gas1, and that this pathway may represent a new target for more effective therapies to prevent relapses and progression in Multiple Sclerosis.
I choose to join the UMR Inserm U1034 to bring together my deep BBB knowledge and its unique expertise in Hedgehog signaling and vascular biology. Moreover the Bordeaux University, through its internationally recognized neuroscience campus, offers me an exceptional opportunity to develop fruitful collaborations with many distinguished researchers.
My project is voluntarily built towards the exploitation of novel dynamic in vitro/in vivo BBB models requiring original microfluidic chamber design and 2-Photon live imaging (secondment in M. Nedergaard’s laboratory, Copenhagen), in vivo explorations of yet unpublished transgenic mice using high resolution imaging tools and the development of new molecules targeting original protein-protein interactions.
As soon as I'll get exciting data, I will disseminate my work through seminars, international conferences and publications in high impact factor journals. Moreover, I will use the opportunities from both my hosting structure and Neurocampus programs to communicate to a wider audience (laboratory visits, meetings, Brain awareness week contributor). Ultimately, this fellowship will establish my emerging status of ""young leader in neurovascular biology"" with an international collaborative network.
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