Projektbeschreibung
Nicht-kanonische DNA-Strukturen bei Trypanosomen im Visier
Die Schlafkrankheit bzw. Afrikanische Trypanosomiasis ist eine vektorübertragene, durch den Parasiten Trypanosoma verursachte Erkrankung, die von der in Afrika südlich der Sahara endemischen Tsetsefliege übertragen wird. Nachdem der Parasit in das Blut- und Lymphsystem eingedrungen ist, infiziert er das zentrale Nervensystem, was tödlich enden kann. Ungeachtet der Tatsache, dass es eine wirksame Ersttherapie gibt, hat die Gefahr einer drohenden Arzneimittelresistenz die Forschungsgruppe des EU-finanzierten Projekts SMART dazu veranlasst, alternative Lösungen zu erkunden. Das Projekt zielt auf Sekundärstrukturen der DNA, sogenannte G-Quadruplexe, ab, die sich normalerweise in der Telomer-DNA vieler Arten bilden. Die Forschenden werden Moleküle entwickeln, die selektiv auf Trypanosomen-G-Quadruplexe abzielen, um deren Rolle in der Trypanosomenbiologie zu untersuchen.
Ziel
African trypanosomiasis (AT), caused by the protozoan parasite Trypanosoma spp., is a debilitating disease that threatens millions of people in Sub-Saharan Africa. The human disease evolves in two stages, the second of which causes a fatal neurological infection if left untreated. The recent discovery of the orally-bioavailable drug fexinidazole, and its current use as a first-line treatment, has significantly improved disease outcomes associated with AT. However, the risk of resistance to fexinidazole treatment is a major concern that highlights the need for new treatment options. G-quadruplexes (G4s) are non-canonical DNA secondary structures that have recently emerged as an attractive target to fight AT. For example, recent studies have revealed the killing properties of a well-characterised G4-ligand, quarfloxin, against T. brucei parasites, showing the great potential for G4-targeting approaches to treat AT. However, the fundamental role of G4s in trypanosome biology and their validation as therapeutic targets have not been elucidated. In this proposal, I aim to unravel the biological functions of G4s in trypanosomes using integrated chemistry and genomic approaches. Specifically, peptide-based molecules designed to selectively target trypanosome G4s (TG4) will be developed and biophysically validated. The TG4-selective peptides will be used to functionally interrogate the trypanosome genome and to understand the effect of G4-modulation on gene expression using transcriptomics. Finally, our peptides will be engineered into fluorescent probes to facilitate real-time molecular visualisations of TG4s formation in vitro, and to provide an in-depth characterisation of these structures as novel targets to combat AT.
Wissenschaftliches Gebiet
Not validated
Not validated
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
SW7 2AZ LONDON
Vereinigtes Königreich