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: 7022156
• 负责人: ROBERT BITTMAN
• 金额: $ 37.96万
• 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/7022156
• 关键词: biomedical resource; cardiovascular function; cardiovascular pharmacology; chemical synthesis; combinatorial chemistry; cooperative study; drug discovery /isolation; lipid metabolism; lipid transport; lung; membrane lipids; prodrugs; respiratory function; respiratory pharmacology; sphingolipids; sphingomyelins; sphingosine

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）： 该资源的目标是合成 1-磷酸鞘氨醇 (S1P)、鞘磷脂和鞘糖脂的多种变体，以便与 NHLBI 和其他研究与心血管和肺生物学相关的研究人员合作。待制备的类似物包括 S1P 和 FTY720-磷酸盐的磷酸盐和光亲和探针，FTY720-磷酸盐是一种免疫抑制前药，与 S1P 一样，由鞘氨醇激酶产生，然后靶向特定的质膜受体。该申请描述了十八个项目，这些项目将通过获得独特的鞘脂而得到促进。其中一些项目的目标包括鉴定 S1P、精神氨酸和鞘氨醇磷酸胆碱受体的配体结合袋。其他目标包括阐明负责以下作用的分子机制：S1P 和 FTY720 调节 T 淋巴细胞功能和感染介导的肺部炎症反应；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；鞘磷脂抑制脂肪分解活性和脂质过氧化；鞘磷脂改变鞘糖脂的跨双层不对称性；以及通过活上皮细胞中的小穴依赖性途径进行鞘糖脂的内化。最后，鞘脂的鞘脂骨架或脂肪酰基链将在特定位点用氘标记，以探测鞘脂与其他膜脂的相互作用，并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在心血管和肺部生物学中具有独特作用的脂质的理解。将制备专门的脂质并在实验中使用，这将提供有关这些脂质特性的急需数据，从而开发出长效化合物以防止肺损伤和心脏损伤。 （摘要完）