This project is directed toward the identification and analysis of the genes affecting the differential susceptibility of different mouse strains to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. TMEV-induced demyelinating disease provides an excellent model for human multiple sclerosis (MS), both at the level of clinical symptoms and of histopathology. The disease occurs as the result of an active cell- mediated immune response, probably delayed type hypersensitivity, against the virus, which results in """"""""innocent bystander"""""""" destruction of myelin. Like human MS, there is a clear genetic influence on the likelihood of disease development, and the identification/analysis of the involved genes may provide clues as to mechanisms (including prevention or alleviation) and other risk factors. These will be especially relevant where the equivalent human genes are known which correlate with those defined in these studies. The analysis will proceed along three lines of inquiry. The first is the use of classical methods of genetic analysis, involving the generation and study of F1 and F2 hybrids and backcross progeny between susceptible and resistant strains to determine which trait is dominant and to make a minimal estimate of the number of relevant segregating loci. Subsequent use of congenic, recombinant, mutant and recombinant-inbred strains will aid in identification and mapping of the loci involved. The second phase is to analyze whether resistant animals fail to develop the disease because (a) they are intrinsically incapable of generating the destructive immune responses against TMEV, or whether (2) they actively inhibit latent responses which, if released from these inhibitory mechanisms, would go on to cause disease. The third phase is to develop RFLP assays for analyzing the roles of specific genes involved in TMEV-induced demyelinating disease and for possible predictive use in identifying which animals, among segregating populations, are at high risk for developing the disease.
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