The underlying pathological mechanisms contributing to the human demyelinating disease Multiple Sclerosis (MS) are poorly understood. Current hypothesis indicate that the etiology of MS is multifactorial and includes the genetic background of the individual as well as environmental influences e.g. viral. Infection of susceptible mice with mouse hepatitis virus (MHV, a positive-strand RNA virus in the Coronaviridae family) results in a chronic demyelinating disease. Animals develop ascending hind-limb paralysis accompanied by mononuclear by mononuclear cell infiltration into the CNS and myelin destruction. As such, the MHV-model of demyelination is considered an excellent model to study the immunopathological mechanisms contributing to demyelination in patients with MS. T cells and macrophages are important contributors to the pathogenesis of MHV-induced demyelination as well as demyelination in MS patients. The long-range goal of this research proposal is to better understand the molecular mechanisms that regulate entry of T cells and macrophages into the CNS. To this end, studies are designed to evaluate the contributions of chemokines and chemokine receptors in the pathogenesis of MHV-induced demyelination. This is particularly relevant as recent studies have implicated chemokines and chemokine receptors in the pathogenesis of MS. Novel strategies designed to accomplish this goal include i) the use of anti-chemokine antibodies that specifically neutralize chemokine activity in vivo within MHV-infected mice, ii) utilization of chemokine and chemokine receptor knock-out (-/- ) mice to evaluate the development of neurologic disease following MHV infection of the CNS, and iii) the instillation of replication deficient adenovirus vectors that express recombinant mouse chemokines into the CNS of mice to better understand the contributions of these molecules in contributing to neuroinflammation and demyelination. Together, these studies will extend our current understanding of how chemokines and their receptors control CNS inflammation and demyelination. Further, the data obtained from these experiments may identify potential targets for therapeutic treatment of humans with MS. Finally, the data obtained from these experiments may identify potential targets for therapeutic treatment of humans with MS. Finally, as chemokines have been implicated in numerous inflammatory pathologies, findings obtained from these studies will be relevant to other human inflammatory diseases.
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