Summary
Multiple sclerosis (MS) is a prevalent demyelinating disease that primarily affects young adults. Current therapy for MS mainly focuses on immune suppression and alleviating inflammation. However, efforts to promote remyelination face challenges in clinical translation. Animal models of acute demyelination have demonstrated promising remyelination, primarily facilitated by newly generated oligodendrocytes. Nevertheless, the scenario in human MS differs, as the disease typically manifests in adulthood and the progression of lesions occurs over several decades.
In the proposed project ResilMS, by using barcode based lineage tracing combined with ultra-depth single-cell and spatial transcriptomics, I will identify the molecular profiles of existing and newly generated oligodendrocytes at different stages of a mouse model induced with experimental autoimmune encephalomyelitis (EAE). The aim is to comprehend how an oligodendroglial cell pool diversifies its subpopulations during prolonged disease challenge, and what are the unique molecular properties for resilient cells to maintain their ability to endure an adverse inflammatory environment and remyelinate. Further, I will perform a screen of single nucleotide polymorphisms (SNPs) associated with risk and severity of MS that might affect genes related to the resilience of oligodendrocytes. To experimentally explore the effect of relevant SNPs, human oligodendrocyte cells (hOLGs) derived from pluripotent cells will be perturbed with CRISPR-based genetic modification and observed for cell profile and functional changes.
The identified SNPs and resilience molecular pathways may play a critical role in disease progression for MS patients. By delving into the mechanisms of resilience of (re)myelinating cells in a long disease course, this project will provide valuable insights into MS-related genetic risk and protective factors, and potentially advance diagnostic and therapeutic approaches in MS research.
In the proposed project ResilMS, by using barcode based lineage tracing combined with ultra-depth single-cell and spatial transcriptomics, I will identify the molecular profiles of existing and newly generated oligodendrocytes at different stages of a mouse model induced with experimental autoimmune encephalomyelitis (EAE). The aim is to comprehend how an oligodendroglial cell pool diversifies its subpopulations during prolonged disease challenge, and what are the unique molecular properties for resilient cells to maintain their ability to endure an adverse inflammatory environment and remyelinate. Further, I will perform a screen of single nucleotide polymorphisms (SNPs) associated with risk and severity of MS that might affect genes related to the resilience of oligodendrocytes. To experimentally explore the effect of relevant SNPs, human oligodendrocyte cells (hOLGs) derived from pluripotent cells will be perturbed with CRISPR-based genetic modification and observed for cell profile and functional changes.
The identified SNPs and resilience molecular pathways may play a critical role in disease progression for MS patients. By delving into the mechanisms of resilience of (re)myelinating cells in a long disease course, this project will provide valuable insights into MS-related genetic risk and protective factors, and potentially advance diagnostic and therapeutic approaches in MS research.
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| Web resources: | https://cordis.europa.eu/project/id/101150016 |
| Start date: | 01-06-2024 |
| End date: | 31-05-2026 |
| Total budget - Public funding: | - 206 887,00 Euro |
Cordis data
Original description
Multiple sclerosis (MS) is a prevalent demyelinating disease that primarily affects young adults. Current therapy for MS mainly focuses on immune suppression and alleviating inflammation. However, efforts to promote remyelination face challenges in clinical translation. Animal models of acute demyelination have demonstrated promising remyelination, primarily facilitated by newly generated oligodendrocytes. Nevertheless, the scenario in human MS differs, as the disease typically manifests in adulthood and the progression of lesions occurs over several decades.In the proposed project ResilMS, by using barcode based lineage tracing combined with ultra-depth single-cell and spatial transcriptomics, I will identify the molecular profiles of existing and newly generated oligodendrocytes at different stages of a mouse model induced with experimental autoimmune encephalomyelitis (EAE). The aim is to comprehend how an oligodendroglial cell pool diversifies its subpopulations during prolonged disease challenge, and what are the unique molecular properties for resilient cells to maintain their ability to endure an adverse inflammatory environment and remyelinate. Further, I will perform a screen of single nucleotide polymorphisms (SNPs) associated with risk and severity of MS that might affect genes related to the resilience of oligodendrocytes. To experimentally explore the effect of relevant SNPs, human oligodendrocyte cells (hOLGs) derived from pluripotent cells will be perturbed with CRISPR-based genetic modification and observed for cell profile and functional changes.
The identified SNPs and resilience molecular pathways may play a critical role in disease progression for MS patients. By delving into the mechanisms of resilience of (re)myelinating cells in a long disease course, this project will provide valuable insights into MS-related genetic risk and protective factors, and potentially advance diagnostic and therapeutic approaches in MS research.
Status
SIGNEDCall topic
HORIZON-MSCA-2023-PF-01-01Update Date
12-03-2024
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