Project description
Links between genetics and the environment in vascular disease
Moyamoya disease (MMD) is a rare disorder that leads to artery blockage and, eventually, stroke. The genetic cause of MMD is linked to mutations in the Ring Finger Protein 213 (RNF213). Surprisingly, RNF213 was recently shown to play antimicrobial roles. With funding by the European Research Council, the MULTIMOYA project will investigate the potential new link between genetic background and environmental triggers suggested by this evidence. Project investigators will study genes, proteins and metabolites in the immune cells of MMD patients exposed to microbial infections. Through validation of the affected molecular pathways, the project aims to help scientists understand how immune responses relate to vascular disease.
Objective
This project aims to characterize a recently discovered link between a rare genetic disorder of the brain, called Moyamoya disease (MMD), and the cellular immune response against microbial infections. MMD is characterized by a progressive occlusion of arteries at the base of the brain leading to stroke. Mutations in Ring Finger Protein 213 (RNF213) represent the most common genetic cause of MMD, however, it is suggested that environmental stimuli are needed to trigger disease onset in genetic carriers.
Intriguingly, we recently discovered RNF213 as a novel antibacterial protein that can target intracellular Listeria (Gram+), providing strong protection to Listeria both in vitro and in vivo. Similarly, RNF213 can bind intracellular Salmonella (Gram-), mediating its ubiquitin-dependent degradation. Moreover, we also identified RNF213 as a cellular sensor for proteins modified by ISG15 (ISGylated proteins), a ubiquitin-like modification of the immune system induced by interferon. These observations not only uncover RNF213 as a novel key antimicrobial protein, they also suggest an important role for the immune system in triggering MMD.
MULTIMOYA starts from the hypothesis that dysregulated immune responses to infections might trigger MMD disease onset in patients carrying mutations in RNF213. To investigate this hypothesis, we will determine whether MMD patient-derived immune cells respond differently to interferon, LPS or bacterial infection by mapping altered pathways using a multi-omics approach, combining genomics, transcriptomics, proteomics and (tracer) metabolomics data. Results will be validated by biochemical and imaging analysis in relevant patient-derived/like cellular models as well as in mouse models of MMD that we will establish. Together, these experiments will provide unprecedented insight into MMD-related immune responses and fundamental processes that link cellular immunity with vascular disease.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesclinical medicineangiologyvascular diseases
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicineneurologystroke
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
9052 ZWIJNAARDE - GENT
Belgium