Descrizione del progetto
L’interferenza dell’RNA in veste di arma antivirale nei mammiferi
L’interferenza dell’RNA (RNAi) è un meccanismo biologico ampiamente conservato che reprime l’espressione genica ed è mediato da piccole molecole di RNA che si legano agli RNA bersaglio per poi degradarli. Originariamente, tale interferenza era stata definita un meccanismo di difesa contro i virus presenti in vermi, piante e insetti, ma il suo ruolo nei mammiferi rimane controverso. L’obiettivo del progetto UncoveRNAi, finanziato dall’UE, è individuare dove e come si verifica il meccanismo antivirale dell’interferenza dell’RNA nei mammiferi. I risultati forniranno informazioni importanti sulla funzione in vivo dell’RNAi come meccanismo antivirale rispetto agli interferoni di tipo I responsabili dell’orchestrazione delle risposte antivirali nei mammiferi.
Obiettivo
Organisms such as plants, worms or insects rely on RNA interference (RNAi) to mount an antiviral immune response. On the other hand, it is widely believed that the type I interferon (IFN-I) pathway replaced antiviral RNAi as a primary line of defence against viral infections in chordates. However, recent work from multiple teams, including the host laboratory, has described a possible antiviral role for RNAi in cultured mammalian cells and in mice during infection with different RNA viruses. The importance of RNAi as an antiviral mechanism in mammals remains a matter of great controversy, in part due to a dearth of in vivo studies. In particular, the cell type(s) performing RNAi in vivo remains unknown, as is the relative importance of antiviral RNAi compare to the IFN-I response. I propose to decipher the mechanism and importance of antiviral RNAi in mice, by answering three main questions: 1) Where is antiviral RNAi happening? I will identify cell types implicated in antiviral RNAi using reporter viruses and permanent genetic marking of RNAi-competent cells. In parallel with these unbiased approaches, I will study antiviral immune responses in specific cell types likely to rely on antiviral RNAi, such as stem cells. 2) How is antiviral RNAi happening? I hypothesise that antiviral RNAi relies on truncated isoforms of Dicer expressed in specific cell types, and/or production of viral DNA as a means of boosting the RNAi response. I will explore both possibilities in detail. 3) What is the importance of antiviral RNAi? I will specifically ablate antiviral RNAi in cell niches that use this defence mechanism to assess its importance with respect to IFN-I. Overall, my work aims at dissecting antiviral RNAi pathways in mammals and assessing their in vivo significance. This work will provide answers to important questions in the field of antiviral immunity and will potentially open up new areas of research in human health.
Campo scientifico
- medical and health scienceshealth sciencesinfectious diseasesRNA viruses
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsRNA
- natural sciencesbiological scienceszoologymammalogy
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
NW1 1AT London
Regno Unito