Studies in this proposal will determine the location and identity of genes responsible for susceptibility and resistance to experimental allergic encephalomyelitis, an animal model for the human disorder, multiple sclerosis. Experimental allergic encephalomyelitis (EAE) can be induced in the LEW rat strain, but the genetically dissimilar LEW-resistant (LER) and Brown Norway (BN) inbred strains are completely resistant to EAE induction. Our work with backcross rats in this system has led us to conclude that three genetic loci govern the susceptibility of these rats to EAE, and that one of these three determines severity of clinical symptoms. Our objective is to find and identify these genes. After conducting a search of likely candidate genes to explain this inheritance pattern, we have turned to genomic screening technology to help us narrow our search for the three EAE-modifying genes. Genomic screening methods (such as microsatellite mapping) are powerful tools for mapping heritable disease-modifying loci. A successful mapping experiment allows the investigator to exclude large portions of the genome that are not linked to the trait under study, and narrows the focus of subsequent experiments to genomic intervals that are likely to contain a gene of interest. The use of genomic screening in animal models of several disease states (for example, diabetes, hypertension, and epilepsy) has led to the location of multiple disease-modifying loci. This type of screening has the further potential for allowing the eventual cloning of such genes. The considerable homology between the organization of rat and human genomes and the similarities between EAE and the human demyelinating disease lend considerable credence to the hypothesis that genes found to be important in rat EAE will be important in multiple sclerosis as well. All of these features make the application of large-scale genomic methods to samples from our extensive collection of backcross rats segregating for the EAE trait an ideal combination for meeting our goal.
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