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Translational Control Decoded: Predictive, Interpretable and Generative Models of mRNA Regulation

Obiettivo

Current models present an increasingly complex picture of mRNA translation, in which several pathways work together to define protein output in a context-dependent way. Disruptions can lead to disease, yet we are only beginning to crack the combinatorial code that links mRNA features to correct translation levels. Yet, translation is characterized by a confined and modular cis-regulatory space, making it ideal for dissecting function with cutting edge genomics and machine learning (ML).

TRANS-DECODE will deliver a systematic, data- and model-driven strategy for decoding the regulation of mRNA translation at unprecedented resolution and interpretability. Our innovative approach will combine high-throughput massively parallel reporter assays (MPRAs), ribosome profiling, and CRISPR based validation screens with explainable AI and RNA foundation models. We will use iterative design-build-test cycles in human cells and zebrafish as vertebrate model to construct interpretable, predictive models of translation initiation, elongation, and mRNA stability. The project is structured into four ambitious and synergistic aims:

1. Determine the RNA sequence/structure determinants of translation initiation in 5’UTRs using MPRAs and interpretable ML.
2. Connect sequence features to regulatory pathways by perturbing translation initiation factors.
3. Dissect spatial-temporal translation control in vertebrates by adapting MPRAs to spatial single-cell resolution in zebrafish development.
4. Develop generative models of translation that encompass initiation, elongation, and RNA stability to identify pathogenic sequence variants.

The insights gained will not only unravel the molecular logic of translation and open new paths to correct non-coding mutations in human disease, but also enable a directed design of RNA for therapeutic and synthetic biology applications. This will position the project as a blueprint for an AI-driven systematic dissection of cis-regulatory mechanisms.

Campo scientifico (EuroSciVoc)

Parole chiave

Programma(i)

Argomento(i)

Meccanismo di finanziamento

HORIZON-ERC - HORIZON ERC Grants

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Invito a presentare proposte

(si apre in una nuova finestra) ERC-2025-ADG

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Istituzione ospitante

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Contributo netto dell'UE
€ 2 487 317,00
Indirizzo
ROBERT ROSSLE STRASSE 10
13125 Berlin
Germania
Regione
Berlin Berlin Berlin
Tipo di attività
Research Organisations
Collegamenti
Costo totale
Nessun dato

Beneficiari (1)