This program project is a multidisciplinary investigation designed to enrich our understanding of fundamental phenomena which relate to the causes and treatment of mental retardation and related disorders of human development. The overall basic research goal is to increase our knowledge of events in nervous system development and to apply the results to the elucidation of the pathophysiology of disease leading to abnormal brain development. The seven subprojects focus on the roles of glycoconjugates and hormone receptors in neural development, the expression and function of neural plasma membrane proteins and the biochemistry and genetics of lysosomal enzyme deficiencies. The approach in each of these projects includes a combination of basic science and disease related questions. Two projects involve investigations on the role of glycolipids and glycoproteins in the development of the nervous system. By chemical and immunologic techniques, several stage specific, complex neutral glycolipids and gangliosides, not previously detected in the nervous system, have been found. A full spectrum of studies involving their isolation, structural analysis, stage dependent expression and biosynthesis is planned. The use of samples from fucosidosis patients will help in the elucidation of the potential role of fucolipids in normal brain development. In another set of projects, two different plasma membrane proteolipids will be studied. In one instance, as part of an understanding of the structure and function of CNS myelin and its role in the normal development of the nervous system, the mechanisms of an important post translational modification of the myelin proteolipid protein, namely fatty acid acylation of the apoprotein, will be studied. In the other instance, the regulation of the biosynthesis and expression of a plasma membrane cation channel-forming proteolipid will be studied in neuronal systems. Another set of subprojects investigates the biochemistry and genetics of inherited nervous system disorders. The cell biology, enzymology and molecular biology of metachromatic leukodystrophy and globoid cell leukodystrophy will be studied. Another project seeks to explain the unique effects of sex steroids on brain, using testicular feminization mouse mutants as a model. These steroids influence neurogenesis and differentiation and disorders of hormonal metabolism are associated with developmental problems and mental retardation.
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