Projektbeschreibung
Genetische Erkenntnisse über Multiple Sklerose
Multiple Sklerose (MS) ist eine Autoimmunerkrankung, bei der die Myelinscheide um die Axone im zentralen Nervensystem angegriffen wird. Bei genomweiten Studien wurden verschieden genetische Varianten bestimmt, die das Risiko für MS beeinflussen. Sie stehen hauptsächlich mit Immunzellgenen in Zusammenhang. Finanziert über den Europäischer Forschungsrat wird im Projekt SingleMS mittels Einzelzell-Omik die aktive Rolle von Oligodendrozyten, den Zellen, die Myelin produzieren, erforscht. Im Mittelpunkt steht die Chromatin-Zugänglichkeit und die Genexpression dieser genetischen Varianten, die mit den Einzelnukleotid-Polymorphismen bzw. Varianten in Verbindung gebracht werden. Aus der Charakterisierung der transkriptomischen und epigenomischen Umgebung menschlicher Oligodendrozyten werden wichtige Erkenntnisse zum Krankheitsverlauf von MS hervorgehen, sodass möglicherweise Behandlungsstrategien erarbeitet werden können.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
17177 Stockholm
Schweden