Multiple sclerosis (MS) is the major inflammatory disease of the central nervous system (CNS) in humans. Both environmental and genetic factors contribute to what is believed to be primarily an immunopathologic etiology. Although environmental factors are important in disease pathogenesis, they can only exert their effects in genetically permissive hosts. Identification and molecular characterization of disease susceptibility genes in experimental allergic encephalomyelitis (EAE), the principle animal model of MS, will lead to a better understanding of the interplay between such factors in the immunopathologic pathways leading to disease. By extension, we propose that homologous genes, or other genes in the pathways to which they belong, will also be relevant to susceptibility to MS. The long-term goal of the research proposed by Drs. Teuscher and Blankenhorn in this application is to functionally characterize the immunoregulatory genes which govern the phenotypic expression of EAE in the mouse. In order to isolate, identify, and study these genes, they must first be precisely located on the chromosomes encoding them, a goal best achieved using molecular genome exclusion mapping with DNA-based markers. Towards this end, the investigators will utilize DNA from large EAE phenotyped segregating populations and panels of previously mapped simple sequence length polymorphisms (SSLPs) or microsatellites. Ultimately, the findings of the research proposed in this application will lay the foundation required to elucidate, at the molecular level, the relationships between novel immunoregulatory genes and their mechanisms of action, particularly in the area of neuroimmunology.
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