The project addresses an important problem - multiple sclerosis (MS), which is the most common cause of neurological disability in young adults after trauma. While the approval of numerous immunotherapies has had an impact on reducing inflammatory disease activity in relapsing remitting MS, there are no therapies to date that enhance repair of the myelin or markedly influence the progressive stage of the disease. Although non-inflammatory mechanisms may contribute to progressive MS, several recent papers highlight a critical role for ongoing inflammation within the brain at or next to sites of tissue injury. A direct pathogenic role for T cells in progressive MS has been suggested by the presence of lymphoid meningeal follicles, which are associated with cortical demyelination and thinning. A more detailed understanding of how immune cells inhibit remyelination is critical for developing therapies to enhance remyelination and halt progressive MS. Despite observational evidence that immune cells may suppress or promote remyelination, there is remarkably little known regarding the specific mechanisms by which these processes occur. This project addresses a barrier to progress in the field because our understanding of why remyelination fails in disease is presently limited because we have not elucidated the pathways involved in failed oligodendrocyte precursor cell (OPC) differentiation. We plan to pursue an exciting novel observation that not only do OPCs fail to differentiate into myelin producing cells, but in an inflammatory environment they adopt an immune phenotype (iOPCs) and can prime CD8 T cells, as well as become targets of the cytotoxic lymphocytes (CTL). This represents a paradigm shift in thinking about OPC biology and remyelination. We will characterize the profile, fate and function of iOPC. We seek to understand the mechanisms by which they activate CD8 T cells that in turn kill a subset of the iOPC as target cells. We will track iOPC using fate mapping strategies and two-photon intravital microscopy through cranial windows.
We aim to develop drug therapies that target the NFkB signaling pathway involved in MHC expression using several novel therapeutic approaches including the type 2 diabetes mellitus drug exenatide and an agonist of the NLRX-1 signaling molecule that normally regulates NFkB expression.
In this proposal, we propose to characterize the profile, fate and function of inflamed oligodendrocyte precursor cells (iOPC) that fail to repair myelin and instead develop the capacity to activate cytotoxic CD8 T cells in the brain. We aim to develop therapies that specifically target the signaling pathways leading to the dysregulated iOPC phenotype in order to suppress the damage and facilitate myelin repair.
Showing the most recent 10 out of 22 publications
