Projektbeschreibung
Die Erkennungswege des angeborenen Immunsystems des Menschen entschlüsseln
Eines der Kennzeichen der antiviralen Abwehr ist die Identifizierung fremder Nukleinsäuren durch Pattern-Recognition-Rezeptoren, die sich auf Zellen des angeborenen Immunsystems befinden. Durch diese Identifizierung werden Reaktionen der Sensorzelle bis hin zum Auslösen von adaptiven Immunantworten angestoßen. Das vom Europäischen Forschungsrat finanzierte Projekt GENESIS will die Nukleinsäure-Sensorwege in menschlichen Zellen untersuchen. Die Forschenden werden eine Hochdurchsatz-Plattform für Genom-Targeting für groß angelegte Loss-of-Function-Studien entwickeln. Sie werden die Rolle, die Kooperativität und die Redundanz von Nukleinsäure-Sensorwegen sowie die nachgeschalteten Signalereignisse untersuchen. Es wird erwartet, dass die Ergebnisse gänzlich neue Einblicke in die Signalwege des angeborenen Immunsystems in menschlichen Zellen ermöglichen werden.
Ziel
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.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesbasic medicineimmunologyautoimmune diseases
- natural sciencescomputer and information sciencesartificial intelligencepattern recognition
- natural sciencesbiological sciencesgeneticsRNA
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
80539 Muenchen
Deutschland