Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY Viruses are well-established causes of central nervous system (CNS) disease in the most vulnerable populations, particularly in the young and immunocompromised. During CNS infection, the immune response can inadvertently cause neuropathology, resulting in neuronal death and demyelination. Mouse models of viral infection have served as a valuable tool for dissecting mechanisms of demyelinating disease in the adult brain, and a rich body of literature has revealed a complex role for the immune response in demyelination. However, we know little about how viruses disrupt myelination in childhood, when both neurons, oligodendrocytes (OLs), and immune cells are actively maturing. Thus, true myelin restoration remains an elusive therapeutic goal in demyelinating diseases at all ages. The long-term goal is to identify mechanisms to support the preservation and repair of brain cells in the very young. The overall objective of this project is to evaluate the response of oligodendrocyte precursor cells (OPCs), which ultimately give rise to myelinating OLs, during a viral infection in the developing brain. Using a juvenile mouse model of neuron-restricted virus infection, where OPCs/OLs are bystanders to the antiviral immune response, we have found that OPCs expand dramatically during infection, and infiltrating adaptive immune cells are primary drivers of this OPC response. The general hypothesis is that OPCs are spurred to proliferate by infiltrating B cells during a juvenile infection, but that full-fledged OPC differentiation is ultimately impeded by virally-infected neurons. The general hypothesis will be tested via the following the specific aims: (1) determine the protective role of juvenile immune cells in promoting OPC proliferation; and (2) define the role of OPC maturation in recovery from demyelination during a juvenile infection. In Aim 1, we will use genetic and molecular approaches to define how OPC proliferation and maturation are regulated by subsets of B cells over the course of a juvenile infection. In aim 2, we will assess how virally-infected neurons regulate the differentiation of newly-generated OPCs using in vivo and in vitro approaches. The expected outcomes are that we will define cellular and molecular interactions that direct OPC fate during a juvenile viral infection. Collectively, these results are expected to have a significant impact by providing a basis for the development of therapies to preserve or restore myelination in the young brain. This research aligns with NIND's mission by generating fundamental insights into interactions between the brain and immune cells, and by applying that new knowledge to reduce the burden of neurological disease in the most vulnerable populations.
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