Directed Evolution to Understand and Engineer Bioactive Long Noncoding RNAs

Objetivo

Directed evolution (DE) is a uniquely powerful approach for mapping sequence to function and engineering potent biomolecules. Yet despite transforming diverse fields, DE has never been applied to the most numerous class of human genes: long non-coding RNAs (lncRNAs). LncRNA research is stalled at the ‘sequence-function gap’. Until we can connect sequence to cellular phenotype, lncRNAs’ biology will remain opaque and their therapeutic potential untapped.
To break this barrier, I will pioneer the directed evolution of lncRNAs by developing DELFIN - the first technology platform for continuous, multi-cycle evolution of lncRNAs in their native cellular context. DELFIN will deliver experimental fitness landscapes for lncRNAs and ‘Enhanced lncRNAs’ with potent bioactivity. These will allow us to study lncRNAs’ evolutionary principles, connect them to underlying molecular mechanisms, and train predictive models for de novo design. DELFIN is inherently scalable to hundreds of lncRNAs in parallel. Its feasibility is underpinned by extensive preliminary data, which has already de-risked the core methodological innovations.
As a proof of concept for its translational applications, I will apply DELFIN to the urgent unmet medical need of liver disease, evolving hepatoprotective Enhanced lncRNAs and confirming their therapeutic efficacy in clinically-relevant disease models.
REVOLVER offers a dual breakthrough. First, it will deliver the first ever sequence-function maps for this major class of human genes, transforming our fundamental understanding. Second, it will establish a powerful yet practical platform, applicable across the widest range of RNA types and biological contexts, to systematically decode and engineer functional RNAs. REVOLVER will finally crack the design principles of lncRNAs, establishing an evolution-driven paradigm to explore the non-coding genome and engineer a new generation of RNA medicines.

Ámbito científico (EuroSciVoc)

Este proyecto aún no se ha clasificado con EuroSciVoc.
Sugiera los ámbitos científicos que considere más relevantes y ayúdenos a mejorar nuestro servicio de clasificación.