The major objectives of this project are to study the distribution, structure, metabolism, and function of glycosphingolipids (GSLs), particularly gangliosides, in normal and pathological tissues, cells and subcellular organelles of the CNS. We will engage in the isolation and characterization of new GSLs and in the elucidation of new biosynthetic pathways. We will develop new methodologies for investigating their subcellular localization and turnover, and for their chemical synthesis. We will also develop new strategies for elucidating their primary and secondary structures and relate this information to their functional role in biological membranes. The relationship between myelin and oligodendroglia will be examined through the metabolism of components that are intrinsic to these two compartments during brain development. Special emphasis will be placed on the functional role of myelin lipid-protein interactions in myelination and the maintenance of myelin membrane integrity. The mode of myelin lipid-protein interaction will be investigated by such physical techniques as nuclear magnetic resonance spectrometry and differential scanning calorimetry. This knowledge is essential in understanding the physiological role of myelin-associated neuraminidase and the regulation of proteolysis of myelin basic protein myelination and demyelination. Finally, we will investigate the pathogenesis of slow virus agents by studying the composition and metabolism of membrane ganglioside in scrapie mouse brains. We also plan to investigate the expression of gangliosides in a variety of neurological diseases and in an animal model which exhibit astrocytosis in order to better understand the relationship between abnormal ganglioside metabolism and physiological dysfunction in these neurological disorders.
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