Synthesis of Novel Bioactive Sphingolipids as a Resource

新型生物活性鞘脂作为资源的合成

• 批准号: 7367138
• 负责人: ROBERT BITTMAN
• 金额: $ 37.38万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-06 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367138
• 关键词: Alveolar; Biological Assay; Biology; Cardiac; Cardiovascular system; Cell membrane; Collaborations; Data; Deuterium; Development; Epithelial Cells; Glycosphingolipids; Goals; Immunosuppressive Agents; Infection; Inflammatory Response; Label; Life; Ligand Binding; Lipid Peroxidation; Lipids; Lung; Lymphocyte Function; Mediating; Membrane Lipids; Molecular; Pathway interactions; Prodrugs; Property; Psychosine; Range; Research; Research Personnel; Resources; Site; Sphingolipids; Sphingomyelins; Sphingosine-1-Phosphate Receptor; Standards of Weights and Measures; T-Lymphocyte; Variant; Vertebral column; analog; inorganic phosphate; lipid transport; lung injury; novel; phosphonate; receptor; research study; sphingosine 1-phosphate; sphingosine kinase; sphingosine phosphorylcholine; stable isotope

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.

该资源的目标是合成 1-磷酸鞘氨醇的多种变体 （S1P）、鞘磷脂和鞘糖脂将可用于与 NHLBI 和其他研究与心血管和肺生物学相关的研究人员。这 待制备的类似物包括S1P和FTY720-的磷酸盐和光亲和探针 磷酸盐，一种免疫抑制前药，与 S1P 一样，由鞘氨醇激酶产生， 然后针对特定的质膜受体。该应用程序描述了十八个项目 将通过获得独特的鞘脂来促进。其中一些项目的目标 包括识别 S1P、psychosine 受体的配体结合口袋，以及 鞘氨醇磷酸胆碱。其他目标包括阐明分子机制 负责：调节 T 淋巴细胞功能和感染介导的炎症 S1P 和 FTY720 在肺部的反应；磷酸鞘脂类似物的心脏保护作用； 变形诱导的肺泡上皮细胞脂质运输；抑制脂肪分解活性和脂质 鞘磷脂的过氧化作用；改变鞘糖脂的跨双层不对称性 鞘磷脂；以及通过活体中的小穴依赖途径进行鞘糖脂的内化 上皮细胞。最后，鞘脂的鞘骨架或脂肪酰基链将被标记 在特定位点用氘探测鞘脂与其他膜脂的相互作用，并用于 用作稳定同位素稀释测定中的内标。 这项研究旨在增强我们对脂质的了解，这些脂质在以下方面具有独特的作用： 心血管和肺生物学。将制备专门的脂质并将其用于实验中 将提供有关这些脂质特性的急需数据，从而促进 长效化合物可防止肺损伤和心脏损伤。