Objective
Human diseases can emerge from evolutionary trade-offs, when the fitness advantage associated with natural selection of a trait is balanced out by another trait that reduces fitness. KILLBILL builds on this biological principle by reframing jaundice as an adaptive defense mechanism. Regarded historically as a symptom, we discovered that unconjugated bilirubin, the hallmark of jaundice, provides dual protection against malaria: it kills Plasmodium while shielding host tissues from ferroptosis, an iron-dependent cell death pathway causing organ damage. These salutary effects extend beyond malaria, towards sickle cell disease - an inherited hemolytic condition shaped by malaria. We hypothesize that bilirubin contributes to sickle hemoglobin's anti-malarial effect while protecting from hemolysis-induced pathology in sickle cell disease. KILLBILL will define the molecular logic of this dual protection with the potential to translate it into an evolution-informed therapeutic framework. This will be achieved through innovative experimental systems, encompassing genetically modified mice with controlled levels of jaundice and transgenic parasites reporting on bilirubin sensing to link bilirubin targeting with parasite outcomes. Multi-omics and computational modeling will map parasite and host bilirubin-responsive pathways, while proteome-wide assays and genetic manipulation will validate these functionally. We will zoom in the host, focusing on pathways whereby bilirubin regulates ferroptosis and anti-malaria immunity, probing how bilirubin contributes to the anti-malarial effect of sickle hemoglobin and validating ferroptosis as a therapeutic target in both malaria and sickle cell disease. KILLBILL explores bilirubin-responsive molecular vulnerabilities to deliver the blueprints for future dual-action therapeutic strategies reducing pathogen burden and protecting host tissues, towards evolution-informed drug discovery in malaria and beyond.
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.
- medical and health sciences health sciences infectious diseases malaria
- medical and health sciences medical biotechnology genetic engineering
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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.
1649-035 LISBOA
Portugal
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.