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: 7175491
• 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/7175491
• 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; abstracting; analog; inorganic phosphate; lipid transport; lung injury; novel; phosphonate; receptor; research study; sphingosine 1-phosphate; sphingosine kinase; sphingosine phosphorylcholine; stable isotope

DESCRIPTION (provided by applicant): 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. (End of Abstract)

描述（由申请人提供）： 该资源的目的是综合各种鞘氨醇1-磷酸盐（S1P），鞘磷脂和糖磷脂，这些变体将用于与NHLBI和其他研究人员合作，其研究与心血管和肺生物学相关。要制备的类似物包括S1P和FTY720-磷酸盐的磷酸和光接触探针，这是一种免疫抑制作用，像S1P一样，由鞘氨醇激酶产生，然后靶向特定的质膜受体。该应用程序描述了十八个项目，这些项目将通过访问独特的鞘脂。其中一些项目的目标包括鉴定S1P，Psychosine和Sphingosyl磷脂受体的配体结合口袋。其他目标包括阐明负责的分子机制：调节T淋巴细胞功能以及S1P和FTY720肺中感染介导的炎症反应；鞘脂磷酸盐类似物的心脏保护；变形引起的肺泡上皮细胞中的脂质运输；通过鞘磷脂抑制脂解活性和脂质过氧化；通过鞘磷脂的糖磷脂胆脂磷脂的跨贝伊尔不对称的改变；和糖磷脂的内在化在活上皮细胞中的洞穴依赖性途径。最后，鞘脂的鞘扎骨干或脂肪酰基链将在特定位置标记氘，以探测与其他膜脂质的鞘脂相互作用，并在稳定的异位素稀释测定中用作内部标准。这项研究旨在增强我们对在心血管和肺部生物学中具有独特作用的脂质的理解。专门的脂质将在实验中准备并使用，这些脂质将提供有关这些脂质特性的急需数据，从而导致长效化合物的发展以防止肺损伤和心脏损伤。 （抽象的结尾）