Multiple sclerosis (MS) is a complex disease with a multifaceted etiology and heterogeneous pathology. Demyelinated CNS lesions are the pathologic hallmark of MS and are accompanied by varying degrees of inflammation, reactive gliosis, oligodendrocyte death, axonal loss, complement activation and antibody deposition. Clinical experience with humans who have MS, and work with animal models of demyelinating disease, has demonstrated that significant spontaneous CNS repair can occur after demyelination, even without therapeutic intervention. However, for reasons that are poorly understood, repair often fails or is incomplete. Little is known about the cellular and molecular biology of the repair process or why it so frequently fails. A better understanding of this process and the factors that limit it, will be necessary if we are to develop therapeutic strategies to enhance repair. Recently we have investigated the genetic regulation of CNS repair and remyelination in an experimental model of MS. We have found marked differences in spontaneous repair in different strains of mice ranging from no repair with the development of significant neurologic deficits, to almost complete repair with maintenance of neurologic function. Infection of B10.Q mice with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelination with minimal repair and the progressive accumulation of neurologic deficits. In contrast, we have characterized a second strain, FVB, that shows extensive spontaneous repair, with axonal and functional preservation. This """"""""reparative phenotype"""""""" is easily distinguished by morphologic examination of spinal cord cross-sections from mice after TMEV infection. The phenotype is inherited as a dominant trait in outcrosses with non-remyelinating B10.Q mice. The experiments proposed in this application are focused on characterizing the differences in disease pathology and repair between repairing and non-repairing strains of mice. We will first create bone marrow chimeras between FVB and B10.Q mice to determine whether the reparative phenotype is a property inherent to the function of the immune system or to the cells of the CNS. We will then characterize disease pathology in both strains with regard to three distinct biological processes: 1) the extent, timing and mechanism of axonal loss, 2) the fates of mature oligodendrocytes and the development of oligodendrocyte precursor cells in demyelinated lesions, and 3) the quality of the CNS infiltrating immune response and the role that it plays in disease progression and repair. Relatively little is known about the cellular and molecular biology of spontaneous CNS repair and the characterization of the differences between repairing and non-repairing strains of mice might help to identify the molecular pathways that are central to this poorly understood process. PUBLIC HEALTH REVELANCE Multiple sclerosis is the most common non-traumatic cause of neurologic disability in young adults. Clinical experience with humans who have demyelinating diseases such as multiple sclerosis, and work with animal models of demyelinating disease, has demonstrated that significant spontaneous CNS repair can occur after demyelination, even without therapeutic intervention. Little is known about the cellular and molecular biology of spontaneous CNS repair following demyelinating disease, but we have developed a new model system in mice to study the cell biology and genetics of the repair process. The experiments which we propose will add to our general understanding of the processes of CNS repair and remyelination, and may identify new therapeutic targets for the treatment of human MS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Utz, Ursula
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Mayo Clinic, Rochester
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