Sphingolipids are constituents of mammalian plasma membranes and lipoproteins, and have been implicated, in their roles as signaling molecules, in a myriad of physiological events. These lipids have in common a lipophilic portion, ceramide, which mediates critical aspects of cell survival. Studies with synthetic sphingolipids will have an impact on several areas, especially events related to cell surfaces and disease states. In this proposal, studies are proposed with synthetic sphingolipids for the study of a range of intermolecular interactions in order to obtain mechanistic insight into sphingolipid-mediated processes. The six specific aims are: 1) to elucidate the molecular mechanisms underlying the role of cholesterol and sphingolipids in the low-pH dependent fusion activity of alphaviruses with target membranes, 2) to identify the phospholipid scramblase in platelets with radiolabeled photoactivatable phospholipid probes, 3) to analyze interactions between Vibrio cholerae cytolysin and sphingolipids, 4) to examine the role of the trans double bond in the long chain base of ceramide in targeting of ceramide to the Golgi apparatus and metabolism to sphingomyelin and glycosylceramides, 5) to develop a chemical marker for quantitative determination of sphingolipid mediators using a synthetic deuterated marker, and 6) to examine superlattice formation in bilayers of cholesterol and synthetic sphingomyelin analogs.
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