Multiple sclerosis (MS) is a progressive, neurodegenerative disease of the central nervous system (CNS) mediated by autoreactive immune cells that initiate myelin destruction, which leads to motor and sensory function loss. During remyelination, damaged axons acquire a myelin sheath and recover lost function. Clinically, this process occurs early on and requires the generation of new oligodendrocytes, the myelinating cell of the CNS, from oligodendrocyte progenitor cells (OPCs); however remyelination gradually fails as MS progresses. Despite many advances in the treatment of MS, currently there is not an approved therapy aimed at protecting or restoring the CNS to promote patient recovery. Cytokines and their receptors are expressed physiologically in CNS cells and are critical for proper brain and spinal cord development. Further, immune cells, specifically T cells, are required for nervous tissue sparing and repair in models of CNS injury. In addition, we and others have shown that glia exhibit a degree of heterogeneity between regions of the adult brain and respond differently to cytokines. Although OPCs are known to exhibit regional heterogeneity during development and are known to respond to a variety of cytokines, how OPCs differ in the adult CNS and how specific T cell cytokines impact OPC development and CNS repair remains unclear. Thus, the overall goal of this proposal is to determine the impact of cytokines on OPC differentiation and how the immune response affects repair following demyelination in various regions of the adult CNS. Currently, we are establishing 1) the effects of cytokines expressed in the CNS during MS on OPC and astrocyte co-cultures to determine their responsiveness in vitro and 2) an in vivo murine model of MS in which both the hindbrain and spinal cord are targeted by myelin-specific T cells. Once the independent phase of my research begins, I will continue to use the in vitro culture system and novel murine model to dissect the cellular and molecular components of the immune response that impact the migration, proliferation and differentiation of OPCs as described in this K22 research proposal.
Aim 1 will elucidate how cytokines impact OPC function directly or indirectly, through astrocyte-mediated support. We will also identify specific OPC and astrocyte gene networks that are impacted by cytokine treatment and use these targets to assess in vivo relevance in Aim 2 as we dissect OPC regional heterogeneity during CNS autoimmunity. While this K22 proposal advances my longstanding interest in OPC biology and MS, it will also begin to shift my focus to the interface between the immune and nervous system. In addition, I am fortunate enough to have the support and guidance from an established group of neuroimmunologists, Dr. Robyn Klein, my current mentor, Dr. John Russell, our collaborator, and Dr. Caroline Whitacre, my graduate mentor, to provide scientific guidance, advice on transitioning to an independent position, oversee my scientific progress and guide my career development. Overall, the long-term goal of my future research, as established by this K22 proposal, is to strengthen the appreciation of the neuroimmune connection during CNS autoimmunity and understand how we can utilize these communication schemes to enhance repair and facilitate recovery in MS patients.
/Public Health Relevance Despite many advances in the treatment of multiple sclerosis (MS), currently there is not an approved therapy aimed at protecting or restoring the central nervous system (CNS) following autoimmune insult. As repair of the CNS is key to preventing MS disease progression and patient recovery, this proposal will examine mechanisms by which CNS-invading immune cells promote maturation of myelin-forming precursor cells responsive to cytokines in a direct and indirect manner. Findings from this work will aid in the design of targeted treatment options for the recovery of MS patients, stop the progression of neurodegenerative phases of the disease and uncover new molecular mechanisms by which immune cytokines promote repair of the CNS.
