Objective
Understanding the drivers and pathogenic mechanisms of type 1 diabetes (T1D) is a major challenge of biomedicine. Early stages of the disease are characterized by a type I interferon (IFN-I)-driven innate immune response. In addition, genetic studies have identified risk and protective variants in the double-stranded RNA (dsRNA) sensor IFIH1/MDA5. These observations support viral etiology of T1D, with major implications for prevention and therapy. However, a causal virus has not been identified so far despite extensive efforts. We have recently proposed an alternative model, whereby activation of MDA5 and IFN-I occurs via endogenous, rather than viral, transcripts that form dsRNA structures. Specifically, we hypothesized that impaired ADAR-mediated RNA editing of cellular dsRNA can mimic viral infection and trigger islet inflammation. In support of this innovative model, genetic variants that impair endogenous RNA editing are associated with increased risk of T1D. In addition, we found that disruption of RNA editing in mouse and human pancreatic islets induces a robust IFIH1-dependent inflammation and diabetes, and recapitulates key features of early stage T1D.
We propose to study the mechanisms driving unexplained hallmarks of early-stage human T1D that are observed upon RNA editing disruption in beta-cells. We will investigate how metabolic stress and islet architecture impact selective beta-cell destruction; the basis for age-dependent attenuation of IFN-I responses and disease progression; and the immune components responsible for early-stage T1D features. Finally, we will search for RNA editing defects in pancreatic material from T1D patients and assess the pro-inflammatory potential of candidate unedited dsRNAs in human islets.
Our long-term goal is to uncover fundamental principles governing the relationship between RNA editing, IFN responses and inflammation in islets, to understand their impact on T1D, and to identify new approaches for 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.
- natural sciences biological sciences microbiology virology
- medical and health sciences clinical medicine endocrinology diabetes
- medical and health sciences basic medicine immunology
- engineering and technology electrical engineering, electronic engineering, information engineering electronic engineering sensors
- natural sciences biological sciences genetics RNA
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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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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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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.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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(opens in new window) ERC-2025-ADG
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91904 Jerusalem
Israel
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