Multiple sclerosis (MS) is a neurological disease of major socioeconomic importance in which a viral etiology is strongly suspected. Because of the historical importance of experimental animal models to understanding human disease, investigation of MS models can be expected to lead to clearer insights into the pathogenesis of this human disease. Of the few available experimental animal models of virus-induced demyelination, Theiler's murine encephalomyelitis virus (TMEV) infection in mice is possibly the most relevant to MS. Clearly, a multidisciplinary approach is needed to answer relevant questions about the molecular pathogenesis of TMEV-induced demyelinating disease (TMEV-IDD). This application represents a request for the renewal of a highly successful collaborative research effort examining varying aspects of the pathogenesis and immunoregulation, which has been in effect for the past 16 years. This Program Grant is unique in that it represents a multidisciplinary approach to the study of the molecular pathogenesis of TMEV infection and of its utility as a model of MS. Funding is requested for the continuation of Project 1 (Stephen Miller), Project 2 (Byung Kim) and Project 4 (Howard Lipton), and for the inclusion a new Project 3 directed by William Karpus. Project 1 will determine the mechanisms by which and anatomic location wherein autoreactive myelin-specific T cell responses arise via epitope spreading during persistent CNS TMEV infection, ascertain their functional contribution to chronic disease pathology, define the specificity and mechanisms of specific immunoregulation of TMEV-IDD using peripheral tolerance to virus and myelin antigens, and study endogenous presentation of myelin antigens by peripheral and CNS-resident antigen presenting cells. Project 2 will continue to examine the functional contribution of CD8+ cytotoxic T cells in disease pathogenesis and resistance in susceptible and resistant mouse strains. Project 3 will test the hypothesis that chemokines expressed in the CNS of TMEV-infected mice regulate immune responses including cell migration patterns by determining the mechanisms of chemokine and chemokine receptor expression in function during disease development. Project 4 will continue to investigate the molecular basis of virus-host and virus-cell interactions in TMEV-IDD by identifying the cellular receptors for TMEV and their role in pathogenesis, examine the molecular pathways of TMEV-induced apoptosis in murine macrophages, and map neutralizing immunogenic sites on the TMEV virion. We also request funds for three cores to support these scientific investigations - Administrative (Core A); Immunohistochemical Imaging/Flow Cytometry/Virus Preparation (Core B) and Neuropathology (Core C). Important information relative to the nature, specificity (anti-viral and antiself), and immunoregulation of immune responses involved in susceptibility/resistance to TMEV-IDD, as well as genetic elements involved in cellular susceptibility to virus infection and virus persistence should be forthcoming. These studies should add to our understanding of the etiology and immunopathologic mechanisms of myelin injury in MS, aid in design of specific treatment strategies, and hopefully lead to innovative approaches, which may ultimately link a specific virus(es) with MS.
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