Descrizione del progetto
La potenziale immunogenicità dei retroelementi endogeni
I retroelementi endogeni, residui delle sequenze retrovirali presenti nel genoma umano, vengono trascritti nel corso del ciclo vitale di una cellula. La loro mobilitazione è stata associata a diverse condizioni fisiopatologiche, tra cui infiammazione, cancro e invecchiamento. Il progetto EndoRPHIm, finanziato dal Consiglio europeo della ricerca, sta lavorando all’ipotesi secondo cui questi retroelementi avrebbero anche una finalità fisiologica. I ricercatori approfondiranno il modo in cui vengono rilevati dal sistema immunitario e la loro potenziale capacità di innescare una risposta immunitaria benefica. I risultati forniranno indizi senza precedenti sul ruolo svolto dai retroelementi endogeni nell’immunità.
Obiettivo
Almost half of our genome is occupied by ancient viral sequences that can be mobilized under certain conditions and either jump or copy themselves from one location to another. A group of these mobile genetic elements is called endogenous retroelements. Mobilization of retroelements like LINE1 has been shown to cause cancer via insertional mutagenesis. In recent years LINE1 activation has also been associated with the development of inflammatory diseases and inflammation-driven ageing. This means, we collected substantial evidence that half of our genome can potentially make us sick. Nevertheless, we keep replicating these sequences with every cell division at great energetic cost, suggesting that keeping them provides an evolutionary advantage.
In my project I will investigate if sporadic retroelement transcription in healthy cells serves a physiological role in priming the immune system through the constant sensing of retroelement-derived nucleic acids by intracellular nucleic acid sensors. My team and I will investigate how retroelement transcription is regulated in response daily life stresses like virus infections or DNA damage. I propose that instead of regulating transcription themselves, retroelements are largely regulated by canonical gene expression. In mouse models we will investigate how retroelements are sensed by the innate immune system and if this has functional consequences for establishing protective and pathologic immunity. Furthermore, we will investigate the exact molecular mechanism, by which retroelement-derived single stranded cDNA activates the innate immune system, which is currently not understood. Our project involves the development of a new deep sequencing workflow for identification of the genomic origin of retroelement transcripts and a new mouse model to study endogenous LINE1 elements in vivo.
I believe that my project can fundamentally change our view on the role of endogenous retroelements as modulators of host immunity.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
53127 Bonn
Germania