The overall objective of this application is to study the biochemical and immunological basis of demyelination in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), as well as the biochemical parameters affecting myelination and remyelination. Our emphasis is placed on the role of glycosphingolipids (GSLs) in these events. Since GSLs are localized primarily on the cell surface and are known to undergo cell- specific, developmentally regulated changes, they serve as excellent markers for monitoring cellular events occurring during myelination and demyelination. Their importance in this regard is further underscored by: (a) the discovery that there are unique glycolipid antigens common to the nervous system and the endothelial cells, and (b) certain GSLs are powerful modulators of immune cell growth and differentiation. In the first area of research, a major goal is to provide additional biochemical data on myelin breakdown, the associated gliotic reactions, and remyelination. This is facilitated by the development of several novel and highly sensitive procedures for analyzing specific cellular GSL components. Immunological research in MS has been extensive, and there is strong evidence that an autoimmune mechanism may play an important role in the pathogenesis of this disease. The autoantigen(s) that are involved in myelin and oligodendroglial degeneration in MS have not been clearly defined. We hypothesize that the inflammatory demyelination in MS and EAE may be triggered by autoreactive T cells specific for CNS myelin proteins and glycoconjugates, and by humoral response against target antigens specifically localized in endothelial cells and the CNS. The humoral response against the endothelium may account for the vascular permeability change preceding demyelination. This hypothesis will be tested employing in vitro and in vivo model systems. In the second area of research, we plan to focus on the synthesis of galactocerebrosides (GC) which are highly enriched in myelin. Since there are two types of GC, the possibility exists that they are synthesized by two distinct galactosyltransferases. We plan to purify these two enzymes and to study their subcellular localization, and to elucidate the regulation of the enzyme activities during development by molecular biological techniques. Since galactosyltransferases are apparently found in oligodendroglial plasma membrane and myelin, we propose that they may function as membrane adhesion molecules for the formation of the multilamellar structure of myelin. An understanding of the synthesis and function of galactocerebrosides should enhance our knowledge on factors modulating myelination and remyelination.
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