Project description
A key to immune response and therapy
Nucleic acids play a crucial role in triggering immune responses, adopting a left-handed Z-form under cellular stress. These Z-nucleic acids, including Z-RNA and Z-DNA, are detected by proteins ADAR1 and ZBP1. While ADAR1 dampens immune responses, ZBP1 triggers innate immunity, influencing antiviral defence, cancer immunity, and autoinflammation. Despite its significance, the mechanisms regulating ZBP1 activation remain unclear, hindering therapeutic advancements. Supported by the Marie Skłodowska-Curie Actions programme, the ZIREN project aims to address this gap by generating a ZBP1 agonist, validating its effectiveness in vivo, and identifying key regulators of ZBP1 signalling. This research will illuminate ZBP1’s activation pathways, paving the way for potential therapeutic strategies targeting ZBP1-driven conditions.
Objective
Nucleic acids are potent inducers of an immune response. Nucleic acids normally exist in a right-handed conformation. However, during conditions of cellular stress, nucleic acids can also adopt an unusual, left-handed “Z-form”. These Z-nucleic acids, including Z-RNA and Z-DNA, are sensed by two proteins: ADAR1 and ZBP1. While ADAR1 binding to Z-nucleic acids prevents immune responses, activation of ZBP1 results in the activation of an innate immune response. It is clear, that ZBP1 has important functions in antiviral defence, cancer immunity and during autoinflammation, yet the mechanisms that govern its activation and which pathways downstream of ZBP1 are activated, is poorly understood. Additionally, a big hurdle currently preventing the molecular characterisation of ZBP1 signalling, is the lack of a selective ZBP1 agonist.
I hypothesise that understanding the molecular mechanisms regulating ZBP1 activation and its downstream signalling pathways is fundamental for the development of therapeutics targeting this pathway. To test this hypothesis, I will address three major knowledge gaps in ZBP1 biology: (i) by purification of active ZBP1 complexes followed by nanopore sequencing and through solid-phase nucleic acid synthesis, I will generate a bona fide ZBP1 agonist, (ii) I will validate the ZBP1 agonist in vivo by testing its adjuvanticity in a mouse vaccination model, and (iii) by using a small compound and a genome-wide CRISPR/Cas9 knockout approaches, I will identify upstream and downstream regulators of ZBP1 signalling. Together, my proposed research plan will contribute to understanding the activation mechanisms of ZBP1, as well as its regulatory factors laying the foundation for understanding human ZBP1-driven (patho)physiology and development of therapeutic intervention.
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 basic medicine physiology pathophysiology
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine oncology
You need to log in or register to use this function
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.
-
HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
See all projects funded under this programme
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-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
See all projects funded under this funding scheme
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) HORIZON-MSCA-2024-PF-01
See all projects funded under this callCoordinator
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.
9052 ZWIJNAARDE - GENT
Belgium
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.