Grant: Discovery Grants Program - Individual

The myelin is a multi-layered membrane that ensheathes the axon, enabling rapid transmission of the nerve impulse. Within the myelin membrane there are unique regions or microdomains that are functional entities necessary for proper myelin development and maintenance. The common structural components of microdomains are less-fluid lipids, such as glycosphingolipids and cholesterol. The different types of microdomains vary in their affinity for certain classes of proteins. A specific type of microdomains, lipid rafts are found in most cellular membranes and are enriched in lipid-anchored proteins. Although caveolae have been observed as flask-shaped invaginations in the membrane, this particular microdomain has not been found in myelin or the myelin-producing cells. Other the myelin microdomains such as caveolin-enriched microdomains, gap junctions, and the radial component may be involving in complex signaling networks. To determine the roles of the various microdomains in myelin, it is necessary to separate each type from the bulk membrane and characterize their proteome. With differential extractions techniques we will isolate each microdomain, and with 2D gel electrophoresis and multi-dimensional protein identification analysis we will determine the protein composition. The further analysis of multi-protein complexes will suggest specific functional roles in the development and maintenance of the myelin sheath. From this knowledge we can investigate the remodeling of myelin microdomains in various diseases and disorders of CNS ""white matter"" such as multiple sclerosis or adrenoleukodystropy, and determine molecular targets which can be used in therapeutic strategies.