The human inherited disorders of sphingolipid metabolism (Gaucher disease, Krabbe disease, Niemann-Pick disease, metachromatic leukodystrophy, etc.) are characterized, particularly in their infantile forms, by severe mental retardation, neurological degeneration, and various specific symptoms. Research on these disorders has been severely hampered by the lack of animals bearing the same genetic errors. We hope to induce model versions of the disorders by synthesizing and administering inhibitors of the sphingolipid hydrolases to young rats. The progressive changes in the brain and other organs will be followed by chemical assays, enzyme assays, isotope uptake measurements, and morphological examination. Other compounds will be administered to rats which are known to block the enzymes that form the sphingolipids. It is possible that they will alleviate the model disorders by slowing the rate of accumulation of the lipid whose hydrolysis is blocked. A compound is available which acts as a stimulator of the glucosidase which cleaves glucocerebroside. Its effects will be tested in rats to see if it alleviates the model disorder. It is expected that use of the new compounds will clarify the role of the sphingolipids in normal and pathological human brain operation, as well as other functional roles of these lipids. During the coming year we will concentrate on the enzymes involving glucocerebroside.