Identification of interaction pathways that mediate remyelination and myelin replacement using single cell and spatial multiomics

• Applicant: Dr. Clemens Ries
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578369230

Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS), providing both insulation and metabolic support to axons. In demyelinating diseases like multiple sclerosis (MS), affecting ~2.8 million people globally, OLs and myelin degenerate due to autoimmune attacks, leading to white matter lesions, neuronal loss, and severe motor and cognitive impairments. Recent findings suggest that even “normal appearing white matter” may harbor myelin abnormalities, impacting neuronal survival and disease progression. Effective remyelination is essential, yet the role of axon-derived signals in initiating myelin repair remains poorly understood. INTERACTomics aims to identify interaction pathways mediating neuron-OPC interactions that drive myelination and myelin replacement with potential use for clinical application. Using single-cell and spatial multiomics, I will: (1) Determine the main signaling pathways in neurons sensing their myelination state and how the replacement of diseased myelin is mediated.; (2) Identify interaction pathways mediating myelin replacement modulated in human disease and test them ex vivo; and (3) functionally validate the main candidate pathway in vivo. I will achieve these objectives by combining circuit-specific single cell RNA/ATAC sequencing of layer 2/3 callosal projection neurons and spatial transcriptomics and proteomics analyses along their projections at different myelination states using comparing myelin wildtype, dysmyelinated Shiverer and human glial progenitor cell transplanted Shiverer mice. Candidate pathways will be refined by integrating human MS data, tested ex vivo in slice cultures, and finally validated in vivo using CRISPRi/a and soluble factor application in combination with human glial progenitor cells. This project will generate a multiomic atlas of neuron-OPC interactions, advancing our basic understanding of remyelination and offering novel therapeutic targets, while equipping me with cutting-edge interdisciplinary expertise and ideally preparing me for a future career as independent researcher.

• DFG Programme: Fellowship
• International Connection: Sweden
• Host: Professor Dr. Goncalo Castelo-Branco