Projektbeschreibung
Zur Rolle von RNA-Modifikationen im Lebenszyklus des Malariaerregers Plasmodium
Im komplexen Lebenszyklus des Malariaerregers Plasmodium falciparum sind Mensch und Stechmücke jeweilige Zwischenwirte. Neuere wissenschaftliche Daten belegten bereits die wichtige Rolle der post-transkriptionellen Expressionsregulation für das parasitäre Überleben und Übertragungsgeschehen. Deren genauere molekulare Mechanismen sind hingegen noch kaum erforscht. Schwerpunkt des EU-finanzierten Projekts PlasmoEpiRNA sind die mRNA-Methylierung von Adenosinen (m6A) und die Bedeutung dieser post-transkriptionellen Modifikation für die Zwischenstadien des Parasiten. Geklärt werden soll, welche Determinanten diese mRNA-Modifikationen in die jeweiligen biologischen Signalwege übersetzen, um neue Zielstrukturen im Kampf gegen Malaria zu finden.
Ziel
Post-transcriptional regulation in malaria parasites is key to the progression through different developmental stages of the complex life cycle within the human and mosquito host. This includes the asexual proliferation within human red blood cells that is responsible for all clinical symptoms of the disease and the preparation for the environmental changes accompanying transmission from host to vector and vice versa. Although the process that controls the destiny of mRNA are of critical importance to parasite survival and transmission, the molecular mechanisms orchestrating post-transcriptional regulation on a transcriptome-wide level remain largely unknown. We recently identified extensive methylation of adenosines (m6A) at internal mRNA positions as a new layer of post-transcriptional regulation of gene expression in Plasmodium falciparum. With m6A, the parasite dynamically modulates its transcriptome through selective mRNA degradation and/or translational repression of modified transcripts during blood-stage development. This new epitranscriptomic layer provides a previously missing link between the transcriptional program and the observed post-transcriptional events throughout P. falciparum development. The proposed project aims to elucidate how m6A mediates different outcomes of mRNA at key developmental stages of the parasite life cycle. We will 1) characterize m6A-binding proteins and elucidate how different m6A ‘readers’ translate this mRNA modification into distinct biological pathways (i.e. degradation, repression) during blood-stage development and 2) investigate how m6A and its specific reader proteins designate mRNAs to facilitate transient quiescence in transmission stages (i.e. gametocytes and sporozoites) to ‘prime’ the transcriptome for new host/vector environments. Overall, exploring the epitranscriptome of this parasite will reveal novel principles and molecular determinants of post-transcriptional control that can be targeted to combat malaria.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
75724 Paris
Frankreich