Decoding cell type-specific molecular traits along functional circuits in inflammatory demyelination

• Applicant: Professor Dr. Lucas Schirmer
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466144436

The project proposal has a specific focus on functional circuits that are regularly affected by multiple sclerosis (MS) pathology. MS is a prototypic inflammatory-demyelinating autoimmune disease of the central nervous system (CNS) resulting in permanent neurological disability. Despite great advances in controlling the inflammatory impact on the disease, the precise molecular and cell type-specific traits of pathology and during disease progression are still not known. To address molecular traits along functional CNS circuits, we will put a strong emphasis on ‘homeostatic’ vs. ‘reactive’ neuroglial subtypes and decode how subtypes respond to spatially well-defined inflammatory demyelination over time. In three Scientific Aims that are closely related to each other, we will utilize complementary cell type-specific ‘genomic’ tools such as single-nucleus RNA- and ATAC-sequencing (snRNA/ATAC-seq) and spatial transcriptomics in a top-down manner according to a methodological stepwise refinement.Aim 1 uses region-specific snRNA-seq in combination with snATAC-seq and SNP genotyping to decode neuroglial cell diversity and ‘genomic’ vulnerability along the visual pathway within the same individuals affected by MS pathology.Aim 2 uses neuron-specific snRNA-seq and both a unifocal lesion model (lysolecithin-induced demyelination) and MS samples to decode the transcriptomic response of neuron subtypes in the motor cortex as a consequence of ‘focal’ inflammatory demyelination along the cortico-spinal tract over time.Aim 3 uses neuron subtype-specific snRNA-seq and both a multifocal lesion model (experimental autoimmune encephalomyelitis) and MS samples to decode the transcriptomic response of specific neuron subtypes involved in motor coordination (olivo-cerebellar system) to chronic inflammatory demyelination during EAE disease progression.In summary, this project will help better understand the individual ‘genomic’ risk and vulnerability of neurons subtypes along critical CNS circuits. Further, it will help better assess subtype-specific levels of neuroglial reactivity during under chronic inflammatory-demyelination conditions. These studies will eventually help identify novel cell type-specific biomarkers and therapeutic targets in the context of progressive MS.

• DFG Programme: Research Grants