The major objective of this project is to study the chemistry and metabolism of gangliosides during nervous system development. Earlier studies have demonstrated that the ganglioside composition of mammalian brains changes dramatically during development. Since membrane gangliosides are known to play important roles in diverse cellular functions such as cell-cell interaction and adhesion, growth inhibition, differentiation and proliferation, the strict regulation of their metabolism is required for normal cellular function. As a first step we will define and determine the structures and distributional pattern of these stage-specific glycosphingolipids that are involved in cellular growth and differentiation, particularly during early nervous system development. We will continue to seek new biosynthetic pathways for their synthesis. At present our knowledge on the molecular basis of ganglioside metabolism is limited. To delineate the metabolic basis of the developmental changes in cell surface gangliosides, we will focus on several glycosyltransferases that are situated at the key regulatory points for their synthesis. We will first achieve the isolation and purification of these enzymes in order to study their biochemical and molecular properties. We will further apply immunocytochemical techniques to define their cellular and subcellular localization, and molecular biological techniques to examine how the expression of these enzymes, as a family of closely related gene products, is regulated at various stages of brain development. Since the striking development changes in ganglioside composition of brain cells depend ultimately on an intricate balance in their synthesis and degradation, we will also focus on a key enzyme, neuraminidase, in this process. As neuraminidase is also known to regulate cellular growth and differentiation, we will examine how modulation of ganglioside catabolism by this enzyme may be involved in the regulation of ganglioside expression in developing nervous system. The long-term goal of these studies is to better understand the expression and regulation of cell surface gangliosides in the developing nervous system. An understanding of the molecular mechanisms underlying the differentiation of nerve cells should greatly enrich our knowledge in the function of gangliosides in normal brain development as well as in neurological disorders that result in mental retardation.
Showing the most recent 10 out of 199 publications
