Project description
Deiminase enzymes as novel targets of autoimmune disease
Rheumatoid arthritis (RA) is an autoimmune disease that affects nearly 1 % of the world population. Recent evidence suggests that the family of peptidyl arginine deiminase (PAD) enzymes which catalyse the formation of citrullinated proteins are implicated in disease aetiology. The EU-funded inCITe project is in the process of developing innovative chemical biology and molecular tools to study PAD function and find novel modulators. The overarching aim is to provide fundamental insight into PAD biology alongside novel therapeutic interventions against other PAD-associated diseases, including Alzheimer’s disease, multiple sclerosis, lupus and cancer.
Objective
Roughly 1% of the world’s population is affected by rheumatoid arthritis (RA); a devastating autoimmune disease causing cartilage destruction and bone erosion. Recent evidences suggest that dysregulation of Peptidyl Arginine Deiminase (PAD) levels are associated with the onset of the disease, leading to the production of antibodies targeting the citrullinated neoepitopes. The exact role of each of the PAD isotypes in these pathological processes is unknown and fundamental questions on the intracellular activation mechanism and substrate specificity remain unanswered. Moreover, isoform specific and high affinity enzyme inhibitors are lacking thereby not only hampering fundamental research towards each PAD isotype, but also excluding PAD as a potential therapeutic target for these diseases.
This proposal is aimed at developing innovative chemical biology- and molecular tools to study PAD functioning and protein citrullination in health and disease. The work reflects my interdisciplinary experiences as well as my interest I have obtained over the last years in chemical immunology as well as my ambition to improve patients wellbeing. More detailed, I aim to 1) find unknown PAD modulators, 2) find PAD substrates, 3) find selective and high affinity PAD inhibitors using enzyme-templated inhibitor evolution as novel lead discovery strategy, 4) explore multifunctional targeted PAD ‘nanosponges’ as advanced avidity-based nanomedicine approach and 5) explore unprecedented citrulline ‘eraser’ enzymes by innovative chemical biology strategies.
The workpackages described in this ambitious and highly interdisciplinary proposal deliver high-end molecules and methods that can be used to answer fundamental (conflicting) questions on citrullination and PAD biology. Moreover, possible molecular leads and advanced therapeutic insights are provided thereby centring PAD as therapeutic target for citrulline-mediated autoimmune diseases such as RA.
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 clinical medicine rheumatology
- medical and health sciences basic medicine immunology
- medical and health sciences medical biotechnology nanomedicine
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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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)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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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.
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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.
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Call for proposal
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(opens in new window) ERC-2018-STG
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6525 XZ Nijmegen
Netherlands
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