Unravelling the transcriptional networks of forebrain neural stem cells for novel in silico drug discovery approaches for regeneration in multiple sclerosis

• Applicant: Dr. Kasum Azim
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 355807716

Adult neurogenesis is associated with learning, memory and cognitive performance. However, neural stem cell (NSC) activity in the brain dramatically decreases with age. This decline has been associated with age-related cognitive impairment, neurodegeneration and decreased regeneration in demyelinating diseases, such as Multiple Sclerosis. The aim of this project is to identify transcriptional networks and signaling pathways that can be exploited that regulate NSC differentiation into remyelinating oligodendrocytes in older mice. Could controlling the fate of NSCs evolve as a novel therapeutic strategy in MS? Presently, the most promising and direct approach is to use small molecules to target NSCs for repair in demyelination. Guiding and promoting NSCs into myelinating cells represents therefore a novel strategy for the development of regenerative therapies.The subventricular zone (SVZ) is the main NSC reservoir of the mammalian brain. The dorsal subregions of the SVZ contain NSCs that give rise to distinct neuronal and glial cell populations. Oligodendrocytes, the myelin forming cells of the central nervous system are generated life-long for myelin turnover and plasticity, and originate from the dorsal SVZ. Work leading up to the project has unraveled a dramatic response of the dorsal SVZ for oligodendrocyte replacement, although, in older mice the process of final maturation of remyelinating cells is inefficient. Using high throughput single cell transcriptomics, the work undertaken so far has defined transcriptional networks associated with impaired remyelination in NSCs mice. This essential information was necessary for the identification of therapeutic agents ability to counteract inhibitory transcriptional processes for enhancing remyelination. In the context of on-going DFG funding, this novel aspect has already been realized and represents a potent strategy for overcoming inefficient differentiation during disease. The objectives will be to extend the analysis applied so far by utilising high-throughput for unraveling the temporal transcriptional hallmarks of oligodendrocyte lineage for the precise description of remyelination failure. This information will then be used for the characterisation and integration of pharmacogenomics with gene regulatory networks associated with disease states. Ultimately, this will yield an unparalleled resolution of the mechanistic events underpinning inefficient remyelination and describe the heterogeneity of NSCs and oligodendroglia derived from demyelinated tissue. To our knowledge, such an analysis has so far not been applied in the neurodegenerative context but enables multidisciplinary approaches by combining systems biology and pharmacogenomics strategies as framework investigations relevant to different regenerative medicine fields.

• DFG Programme: Research Grants