The goal of this resource is to synthesize a wide range of variants of sphingosine 1-phosphate (S1P), sphingomyelin, and glycosphingolipids that will be made available for collaborations with NHLBI and other investigators whose studies are pertinent to cardiovascular and lung biology. The analogs to be prepared include phosphonate and photoaffinity probes of S1P and FTY720- phosphate, an immunosuppressive prodrug that, like S1P, is produced by sphingosine kinases and then targets specific plasma membrane receptors. This application describes eighteen projects that will be facilitated by access to unique sphingolipids. The objectives of some of these projects include the identification of the ligand-binding pocket of the receptors of S1P,psychosine, and sphingosylphosphocholine. Other goals include the elucidation of the molecular mechanisms responsible for:modulation of T lymphocyte functions and of infection-mediated inflammatory responses in the lung by S1P and FTY720;cardioprotection by sphingolipid phosphate analogs; deformation-induced lipid trafficking in alveolar epithelial cells;inhibition of lipolytic activity and lipid peroxidation by sphingomyelin;alteration of the transbilayer asymmetry of glycosphingolipids by sphingomyelin;and internalization of glycosphingolipids by a caveolar-dependent pathway in living epithelial cells. Finally, the sphingoid backbone or fatty acyl chain of sphingolipids will be labeled with deuterium at specific sites to probe sphingolipid interactions with other membrane lipids and for use as internal standards in stable-isotope dilution assays. This research seeks to enhance our understanding of lipids that have unique effects in cardiovascular and lung biology. Specialized lipids will be prepared and used in experiments that will provide much-needed data about the properties of these lipids, leading to the development of long-acting compounds to protect against lung injury and cardiac damage.
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