Objective
DNA repair pathways are essential for human health and longevity. While their molecular mechanisms are well defined, their physiological roles across tissues remain less understood. Our foundational research identified a major source of endogenous DNA damage: reactive aldehydes such as acetaldehyde (from ethanol) and formaldehyde (from metabolism and diet), which generate toxic DNA crosslinks in the blood, brain, and kidney. To counter this, cells rely on a two-tier protection system. Tier 1 enzymes (ALDH2 and ADH5) detoxify aldehydes. Tier 2 repairs the damage aldehydes cause via the Fanconi anaemia (FA) pathway or transcription-coupled repair (TCR). Loss of either of these second-tier pathways leads to tissue-specific degeneration, as seen in FA, where blood is most affected, and Cockayne syndrome (CS), where kidney and brain degeneration dominate. In FORCE (Formaldehyde Crosslink Exposure in Genomic Ageing), we build on these discoveries to explore how non-haematopoietic tissues respond to crosslink damage. Using our novel SWITCH mouse models, where Tier 1 detoxification is restricted to blood, we bypass early lethality to reveal hidden vulnerabilities in other tissues. In SWITCH FA-deficient animals, the liver fails due to extreme hepatocyte polyploidy, yet – surprisingly - the rapidly renewing intestine remains unaffected. We will investigate the mechanisms behind hepatic failure and the unexpected resilience of enterocytes, aiming to identify new aldehyde-protective pathways. By contrast, in SWITCH TCR-deficient models, blood-borne formaldehyde detoxification protects against neurodegeneration and kidney failure. We will map the aldehyde-sensitive cell types and examine how systemic clearance preserves tissue function. Finally, we will screen for small molecules that reduce aldehyde toxicity, laying the foundation for new therapies against age-related decline driven by endogenous metabolic damage.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- natural sciences chemical sciences organic chemistry aldehydes
- natural sciences biological sciences genetics DNA
- medical and health sciences health sciences nutrition
- natural sciences chemical sciences organic chemistry alcohols
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2025-ADG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
OX1 2JD Oxford
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.