Description du projet
Décryptage des voies de reconnaissance de l’immunité innée chez l’homme
La détection des acides nucléiques étrangers par les récepteurs de reconnaissance des formes présents sur les cellules du système immunitaire inné constitue l’une des caractéristiques fondamentales de la défense antivirale. Cette reconnaissance engendre des réponses de la cellule sensorielle, jusqu’à l’induction de réponses immunitaires adaptatives. Financé par le Conseil européen de la recherche, le projet GENESIS propose d’étudier les voies de détection des acides nucléiques au sein des cellules humaines. Les chercheurs développeront une plateforme de ciblage génomique à haut débit pour mener des études sur la perte de fonction à grande échelle. Ils exploreront les rôles, la coopérativité et la redondance des voies de détection des acides nucléiques de même que les événements de signalisation en aval. Les résultats devraient fournir des informations inédites sur les voies de signalisation du système immunitaire inné au sein des cellules humaines.
Objectif
In vertebrates, a receptor-based, innate sensing machinery is used to detect the presence of microbederived molecules or the perturbation microbial infection causes within the host. In the context of viral infection, non-self nucleic acids are sensed by a set of intracellular receptors that upon activation initiate broad antiviral effector responses to eliminate the imminent threat. Over the past years our understanding of these processes has considerably grown, mainly by employing murine knockout models.
Recent advances in genome engineering now provide the opportunity to knockout genes or even to perform functional genetic screens in human cells, providing a powerful means to validate and generate hypotheses. We have developed a high-throughput genome targeting and validation platform that allows us to tackle large-scale loss-of-function studies both at a polyclonal as well as an arrayed format. In addition, we have invested considerable efforts to render this technology applicable to study innate immune sensing and signalling pathways in the human system. GENESIS will combine these efforts to tackle pertinent questions in this field that could not have been addressed before: We will systematically dissect known nucleic acid sensing pathways in the human system to explore their unique roles, cooperativity or redundancy in detecting non-self nucleic acids. We will perform polyclonal, genome-wide loss-of-function screens to elucidate signalling
events downstream of intracellular DNA and RNA sensing pathways and their roles in orchestrating antiviral effector mechanisms. Moreover, in a large-scale perturbation study, we will specifically address the role of the kinome in antiviral innate immune signalling pathways, exploring the role of its individual members and their epistatic relationships in orchestrating gene expression. Altogether, these studies will allow us to obtain insight into innate immune signalling pathways at unprecedented precision, depth and breadth.
Champ scientifique
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesbasic medicineimmunologyautoimmune diseases
- natural sciencescomputer and information sciencesartificial intelligencepattern recognition
- natural sciencesbiological sciencesgeneticsRNA
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
80539 Muenchen
Allemagne