This program brings together different scientific disciplines to further elucidate biochemical and generic aspects of processes that relate to mental retardation. The goals of the proposed program stem directly from the previous program project grant with increased focus on the role of glycoconjugates in neural development. This program consists of four closely related and integrated projects. Collectively, these projects address the central postulate that specific, developmentally regulated carbohydrate structures, interacting with cell surface or extracellular receptors, are involved in cellular differentiation and growth regulation during nervous system development. Project 1 will define, in detailed chemical terms, a general class of glycoconjugates, complex neutral glycosphingolipids, that are developmentally regulated and appear in fetal brain and in brain with alpha-fucosidase and beta-galactosidase deficiencies. Glycosyltransferases that are involved in the synthesis and expression of glycolipids will also be studied. Project 2 will test the role of glycoconjugates binding proteins that participate in the action of these glycoconjugate structures will also be characterized. Project 3 involves glycosyltransferases that participate in the synthesis of neolactoseries glycolipids in the CNS and investigation of factors that regulate these glycolipids in CNS and peripheral nerve. Cell surface receptors that bind to glycosphingolipids will also be defined. Project 4 will utilize the unique characteristics of the regenerating rodent olfactory system to define carbohydrate structures that are characteristic of functional and morphologically defined subsets of neurons. In addition, the hormonal regulation of these cell surface glycoconjugates will be studied in this androgen responsive system. This interdisciplinary, focused approach to study the expression, regulation and function of glycoconjugates in the developing nervous system should enrich our understanding of differentiation and growth processes of the developing CNS that are an essential component of the eventual clinical intervention for neurological disorders that result in mental retardation.
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