Unveiling the functional outcome of single nucleotide polymorphisms and variants in oligodendroglia in multiple sclerosis
| Title | Unveiling the functional outcome of single nucleotide polymorphisms and variants in oligodendroglia in multiple sclerosis |
|---|---|
| Acronym | SingleMS |
| Start date | 2024-01-01 |
| End date | 2028-12-31 |
| Sponsor | European Research Council - Advanced Grant (ERC-AdG) |
| Institution | Karolinska Institutet |
Associated cell lines
Project Description
Multiple Sclerosis (MS) is one of the major neurological disorders affecting young adults. Current treatments are effective in the relapsing-remitting stage of the disease, but not in the progressive stage, to which most patients eventually transition. Despite remyelination driven by oligodendrocytes (OLs) and their precursors (OPCs) being essential for disease remission, research in MS is strongly focused on the immunological component of the disease. Recent findings from my research group indicate that oligodendroglia (OLG, including OPCs and OLs) can transition to immune-like states and that MS-risk single-nucleotide polymorphisms (SNPs) and variants might operate in OLG, suggesting that OLG have a much more important and active role in MS than previously anticipated. In SingleMS, we will delineate in-depth the chromatin and transcriptional landscapes of MS-risk SNPs/variants loci in OLG to identify their putative targets. Using a unique experimental strategy combining genome-editing, single-cell and spatial omics, and functional assays with human OLG and humanized mice models of MS, we will investigate how these SNPs/variants impact diverse functions of OLG. Given the involvement of these SNPs/variants in MS-risk, this project will provide novel and unique insights not only into their role in the etiology of MS, but also in disease progression and remyelination, processes in which OLG are involved. By bridging genome-wide association studies (GWAS) findings to molecular/functional outcomes, we expect SingleMS to lead to major advances in the discovery of novel targets for MS therapies.