Defining mechanisms of disease and repair in a viral model of multiple sclerosis

Abstract: An important unmet clinical need for patients with the demyelinating disease multiple sclerosis (MS) is an effective method for promoting remyelination that can ameliorate clinical symptoms associated with demyelination and restore motor function while limiting immune cell infiltration into the CNS. The long-term objectives of this research proposal are to i) define how chemokine signaling controls neuroinflammation and disease progression, ii) assess the effects of chemokine signaling in regulating oligodendrocyte progenitor cell (OPC) maturation and remyelination, iii) further characterize how engrafted human and mouse neural progenitor cells enhance axonal integrity, promote remyelination and influence neuroinflammation/demyelination, iv) define mechanisms by which microglia restrict the severity of demyelination and influence remyelination. To accomplish these goals, we will use a well-accepted pre-clinical animal models of MS. For over 20 years, my laboratory has used intracranial infection of susceptible C57BL/6 mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) as a model of viral-induced demyelination to study molecular and cellular events controlling neurioinflammation, demyelination, and remyelination. Proposed experimental procedures that will aid in accomplishing our research goals will include genetic approaches through generation of mice in which targeted genes are either selectively induced/ablated to assess effect on disease progression and repair, CRISPR technology to ablate specific target genes in NPC cultures, single cell and nuclear RNA sequencing on immune cells and resident CNS cells and use of 2-photon (2P) microscopy to visualize axonal damage/repair and remyelination. Collectively, we believe our experimental goals outlined in this proposal will provide new insight into the pathogenesis of MS as well as identify new targets for therapeutic intervention to impede disease progression and promote remyelination.