Targeting The Wnt Signalling Pathway To Promote Myelin Repair
Multiple sclerosis is a non-traumatic debilitating disease of the central nervous system (CNS) that affects approximately 2,500,000 people globally and is currently incurable. It is characterised by repeated autoimmune attacks directed at oligodendrocytes and the myelin they produce. This demyelinating disease is characterised by immune dysregulation, destruction of oligodendrocytes and subsequent loss of myelin, loss of axonal support, and eventual degradation of neurons. The neuronal damage during MS is largely irreversible and results in permanent functional deficits. Despite a range of immunological therapies to treat MS, there is no therapeutic option available that repairs neuronal damage. MS aetiology and pathogenesis are complex processes regulated by several cellular signalling pathways. Of these, Wnt/b-catenin signalling regulates key elements of MS pathology such as inflammation and oligodendrocyte differentiation. It is hypothesised that conditionally deleting β-catenin from oligodendroglia will alter both the cell dynamics of OPCs to favour differentiation and subsequent remyelination post toxic demyelination, and the inflammatory milieu in response to toxic demyelination. The study design uses a toxic cuprizone model to induce acute injury to oligodendrocytes and trigger an endogenous remyelination response in which repair mechanisms can be analysed. Using this model, the effect of deleting β-catenin in oligodendrocyte lineage cells prior to demyelination on their subsequent differentiation and cellular distribution will be examined experimentally, as well as how this deletion affects aspects of the immune response to demyelination. It is expected that the conditional deletion of β-catenin from oligodendroglia will alter the cell dynamics of OPCs such that increased differentiation and remyelination post toxic demyelination occurs. Additionally, it is also expected that by blocking β-catenin in the oligodendrocyte lineage cells, the inflammatory milieu in response to toxic demyelination will be altered.