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Future perspectives for glycolipid research in medicine Cox TMPhilos Trans R Soc Lond B Biol Sci 2003[May]; 358 (1433): 967-73Medical interest in glycolipids has been mainly directed to the rare and complex glycosphingolipid storage disorders that are principally caused by unitary deficiencies of lysosomal acid hydrolases. However, glycolipids are critical components of cell membranes and occur within newly described membrane domains known as lipid rafts. Glycolipids are components of important antigen systems and membrane receptors; they participate in intracellular signalling mechanisms and may be presented to the immune system in the context of the novel CD1 molecules present on T lymphocytes. A knowledge of their mechanism of action in the control of cell growth and survival as well as developmental pathways is likely to shed light on the pathogenesis of the glycosphingolipid storage disorders as well as the role of lipid second messengers in controlling cell mobility and in the mobilization of intracellular calcium stores (a biological role widely postulated particularly for the lysosphingolipid metabolite sphingosine 1-phosphate). Other sphingolipid metabolites such as ceramide 1-phosphate may be involved in apoptotic responses and in phagocytosis and synaptic vesicle formation. The extraordinary pharmaceutical success of enzymatic complementation for Gaucher's disease using macrophage-targeted human glucocerebrosidase has focused further commercial interest in other glycolipid storage diseases: the cost of targeted enzyme therapy and its failure to restore lysosomal enzymatic deficiencies in the brain has also stimulated interest in the concept of substrate reduction therapy using diffusible inhibitory molecules. Successful clinical trials of the iminosugar N-butyldeoxynojirimycin in type 1 Gaucher's disease prove the principle of substrate reduction therapy and have attracted attention to this therapeutic method. They will also foster important further experiments into the use of glycolipid synthesis inhibitors for the severe neuronopathic glycosphingolipidoses, for which no definitive treatment is otherwise available. Future glycolipid research in medicine will be directed to experiments that shed light on the role of sphingolipids in signalling pathways, and in the comprehensive characterization and their secretory products in relation to the molecular pathogenesis of the storage disorders; experiments of use to improve the efficiency of complementing enzymatic delivery to the lysosomal compartment of storage cells are also needed. Further systematic screening for inhibitory compounds with specific actions in the pathways of glycosphingolipid biosynthesis will undoubtedly lead to clinical trials in the neuronopathic storage disorders and to wider applications in the fields of immunity and cancer biology.|Animals[MESH]|Glycolipids/*physiology[MESH]|Humans[MESH]|Signal Transduction/physiology[MESH]|Sphingolipidoses/*physiopathology/*therapy[MESH] |
