Description du projet
La génétique contre la sclérose en plaques
La sclérose en plaques (SEP) est une maladie auto-immune qui cible la gaine isolante de myéline des axones au sein du système nerveux central. Des études portant sur l’ensemble du génome ont identifié diverses variantes génétiques associées au risque de SEP, principalement liées aux gènes des cellules immunitaires. Financé par le Conseil européen de la recherche, le projet SingleMS fera appel à la technologie omique de la cellule unique pour étudier le rôle actif des oligodendrocytes, les cellules productrices de myéline. Il se penchera plus particulièrement sur l’accessibilité de la chromatine et l’expression des gènes de ces variantes génétiques liées à ces polymorphismes/variantes d'un seul nucléotide. La caractérisation du paysage transcriptomique et épigénomique des oligodendrocytes humains fournira de précieuses informations sur la pathogenèse de la SEP, ouvrant la voie à de potentielles stratégies thérapeutiques.
Objectif
Multiple sclerosis (MS) is a neurological disease characterized by autoimmune attack targeting oligodendroglia (OLG) in the central nervous system (CNS), and in particular their myelin, which ensheaths neuronal axons. Genome-wide association studies (GWAS) have led to the identification of hundreds of single-nucleotide polymorphisms (SNPs) and variants that are associated with MS risk. Many of these are located near genes associated with immune cells, indicating a key role for these cells in MS. Using single-cell omics approaches, we recently found that OLG present chromatin accessibility or express genes associated with some of these SNPs/variants, both in health and disease. Here, we hypothesize that OLG have a more active role in MS than previously anticipated, and therefore we will determine the function of MS SNPs/variants in OLG in the context of MS, using humanized mouse models, patient samples and new single-cell omics techniques recently developed in my group. We will 1) characterize in-depth the transcriptomic and epigenomic landscape of human and mouse OLG in the context of MS, to identify putative genes affected by the SNPs/variants; 2) perform CRISPR-guided editing of a cohort of the identified SNPs/variants in human OLG, and determine the consequences of the editing at a) an epigenomic and transcriptional level, linking specific SNPs/variants to their bona-fide target genes, and b) a functional level, by performing an array of functional assays targeting myelination, cell survival, and immune function, both in vitro and in humanized mouse chimeras in which engineered human OLG have been transplanted. We will use single-cell and spatial omics technologies, such as nanoCUT&Tag and spatial CUT&Tag, among others which we have recently developed in my research group. The results of this project will yield unique insights into the role of OLG and the identified SNPs/variants in MS, and thereby pave the way to novel therapeutic avenues for this disease.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
17177 Stockholm
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