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Reprogramming inflammation via the DNA damage response-Metabolic axis control

Objectif

Chronic inflammation underlies autoimmune diseases, cancer, and aging. Yet current therapies fail to address underlying metabolic dysregulation of one-carbon metabolism (1C) or unresolved DNA damage triggering oxidative DNA damage response (OxDDR) that fuel persistent immune activation cycles. Here, we want to decode and target the one-carbon metabolism–oxidative DNA damage response (1C–OxDDR) axis, a critical but underexplored driver of persistent immune activation. We hypothesize that chronic DNA damage and rewired 1C metabolism enforce stable, disease-promoting immune phenotypes. To test this, we will map 1C–OxDDR circuits in patient tissues and aging models using multi-omics, spatial transcriptomics, and metabolic flux profiling to define signatures of disease initiation, progression, and therapy resistance. We will identify novel disease drivers and develop precision small molecules, leveraging our track record in developing first-in-class inhibitors to MTHFD1&2, OGG1 and MTH1 using an AI-integrated drug design. Furthermore, we will pioneer catalytic medicine through OGG1 amplizymes, introducing a new therapeutic paradigm that introduces novel enzymatic functions to proteins rather than inhibiting them. These strategies will be validated in advanced preclinical systems, including organoids and humanized models to reprogram immune dysfunction without broad immunosuppression. This high-risk/high-gain program builds on our success in synthetic lethality and PARP inhibitors, aiming to deliver a new precision medicine platform for inflammation-driven diseases. By integrating mechanistic insight with innovative medicinal chemistry, RECODE seeks to break the vicious cycle of chronic inflammation, opening therapeutic opportunities across auto-immunity, cancer, and aging, with impact comparable to our previously discovered paradigm-shifting cancer therapies.

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Mots‑clés

Programme(s)

Thème(s)

Régime de financement

HORIZON-ERC - HORIZON ERC Grants

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Appel à propositions

(s’ouvre dans une nouvelle fenêtre) ERC-2025-ADG

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Institution d’accueil

KAROLINSKA INSTITUTET
Contribution nette de l'UE
€ 2 500 000,00
Adresse
NOBELS VAG 5
171 77 STOCKHOLM
Suède
Région
Östra Sverige Stockholm Stockholms län
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
Aucune donnée

Bénéficiaires (1)