Spatial mapping of MS genetics on affected brain tissue

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Multiple Sclerosis (MS) in an autoimmune neurodegenerative disease affecting more than 2.3 million people worldwide, characterized by localized neuroinflammation leading to loss of the protective myelin sheath covering axons and eventually the formation of demyelinated lesions. MS has a well-defined and extensive genetic component. Our long-term goal is to identify the mechanisms via which MS genetics contribute to disease pathogenesis in the central nervous system (CNS). The overall objective in this application, is to determine key CNS cells that medi-ate genetic associations and respective mechanisms. The central hypothesis is that various CNS cells are affected by the disease genetics and their spatial distribution reflects underlying mechanisms of lesion formation. This hypothesis is formulated based on preliminary results that identified a distinct activation of MS genetics in different cells distributed around MS lesions. The rationale for the proposed research is that the discovery of these CNS cells, and their spa-tial distribution, will lead to a better understanding of the genetic contribution to the disease de-velopment and progression and provide a highly cell-specific list of potential new drug targets. To test the hypothesis and achieve the overall objective, the following specific aims are pro-posed: (i) Identify the cells that are enriched for disease-associated genetics in the affected MS brain. We will generate simultaneously single cell RNA-seq/ATAC-seq from three regions of in-terest (ROIs) of active and inactive MS lesions and control brains, following high-field MRI. We will integrate these data with the most recent MS genetics in order to identify enriched CNS cell, their spatial distribution, and underlying mechanisms. Finally, we will validate these findings uti-lizing genome-wide spatial transcriptomics technologies.