Description du projet
Traitements des maladies cérébrales fondés sur la microglie
La microglie est formée de cellules qui résident dans le cerveau et qui contribuent au maintien de la santé cérébrale et à la modulation de l’inflammation. Le dysfonctionnement de la microglie a été associé à des troubles neurologiques, ce qui en fait une cible thérapeutique privilégiée. La microglie est capable de s’auto-renouveler, ce qui constitue une opportunité unique pour la thérapie cellulaire. Cependant, il n’existe actuellement aucune approche permettant de remplacer spécifiquement la microglie. Financé par le Conseil européen de la recherche, le projet ReplaceMi entend élaborer une stratégie innovante qui permettra de remplacer la microglie embryonnaire en utilisant des progéniteurs spécifiques. Les chercheurs utiliseront des cellules souches pluripotentes induites afin d’identifier les progéniteurs qui parviennent à se greffer efficacement dans le cerveau en tant que microglies. ReplaceMi étudiera également la manière dont la microglie peut se transformer en usine de production de protéines pour traiter les troubles neurodégénératifs et identifiera les réseaux de gènes qui permettent d’améliorer les réponses de la microglie aux maladies.
Objectif
Microglia are highly versatile brain resident cells that offer tremendous therapeutic opportunities. They are instrumental for maintaining healthy brain physiology and act as the primary modulators of neuroinflammation and disease. Microglial dysfunction has been convincingly linked to a myriad of neurological disorders, making these cells a prime target for therapeutic intervention. Remarkably, microglia are embryo-derived cells that self-maintain for life, with negligible replacement by the bone marrow. This astonishing self-renewal capacity offers a unique opportunity for cell therapy. The ability to replace dysfunctional microglia with healthy or genetically enhanced counterparts may transform the way we treat brain disease. But how can we replace a cell that is so adept at self-renewal in a tissue that is shielded from the periphery? Currently there are no translatable approaches for the specific replacement of microglia. Furthermore, bone marrow progenitors are unable to adopt the embryonic microglial phenotype. By building on our unpublished observations and developing innovative technologies, I aim to lay the foundation for microglial replacement therapy. We intend to develop an original and translatable strategy for the specific and near-complete replacement of embryonic microglia with adoptively transferred progenitors. Next, by combining iPSC differentiation with genetic barcoding, single-cell analysis and in vivo screening, we aim to identify progenitors that efficiently traffic to the brain and engraft as bona fide microglia. Moreover, we will investigate how we can transform microglia into local protein production factories, as a potential basis to treat neurodegenerative diseases. Finally, we will set up in vivo pooled CRISPR screens to identify the gene networks that can modulate and positively enhance microglial disease responses. ReplaceMi has the potential to result in a new and eagerly awaited breakthrough in treating brain disease.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
1050 Bruxelles / Brussel
Belgique