Isoeicosanoids& Biologically Active Oxidized Phospholipi

异二十烷酸

• 批准号: 6611191
• 负责人: ROBERT Carl MURPHY
• 金额: $ 22.05万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611191
• 关键词: aerosols; breath tests; chemical structure function; clinical research; eicosanoid metabolism; eicosanoids; human subject; laboratory mouse; leukotrienes; lipid peroxides; macrophage; mass spectrometry; oxidized lipid; peroxidation; phospholipids; prostaglandin endoperoxide synthase

Lipid peroxidation is a naturally occurring process that in part, protects cells and cellular macromolecules from reactive oxygen species. It is now becoming widely appreciated that lipid peroxidation also leads to biologically active products that mediate cellular response to free radical processes. Also, reactive chemical entities are formed during lipid peroxidation that are sufficiently electrophilic to covalently modify proteins and other biopolymers. The overall goal of the proposed research is to explore the initial chemical event taking place during the free radical oxidation of polyunsaturated fatty acids present as phospholipid esters in the membranes of cells. A major focus of the individual studies will center around the oxidation of arachidonic acid as a particularly susceptible target for peroxidative events. Mass spectrometry will be used as the primary tool for structural characterization of oxidized phospholipids. Structural studies of covalent adducts of electrophilic lipid free radical products and target proteins will be carried to determine the site of adduct formation and techniques developed to determine the structure of the lipid portion of the covalent adduct. A second major focus will be developed to determine the structure of the lipid portion of the covalent adduct. A second major focus will be testing the alternative pathway of leukotriene A4. The structural characterization of biologically active phospholipid products of phospholipid oxidation will be a focus of a collaborative project to characterize those oxidized phospholipid products that may induce the anti-inflammatory macrophage phenotype. A second collaborative study will involve the characterization of oxidized phospholipid products that stimulate cyclooxygenase gene induction in endothelial cells. Finally, a method to collect lipid peroxidation products present in aerosols of expired breath in human subjects will be investigated. This novel, non-invasive method will be used to assess lipid peroxidation events in the lung that can be quantitated through measurement of markers using mass spectrometric techniques. Studies of human subjects with upper airway, lower airway, and alveolar lung disease will be undertaken using these techniques of collecting non- volatile molecules in expired breath and quantitation of specific products of arachidonate peroxidation.

脂质过氧化是一种天然发生的过程，部分可保护细胞和细胞大分子免受活性氧。现在，人们广泛认为，脂质过氧化也会导致生物活性产物，可介导细胞对自由基过程的反应。同样，在脂质过氧化过程中形成了反应性化学实体，这些实体足够亲电化，可以重价​​修饰蛋白质和其他生物聚合物。拟议的研究的总体目标是探索在细胞膜中以磷脂酯为磷脂酯的多不饱和脂肪酸的自由基氧化过程中发生的初始化学事件。单个研究的主要重点将围绕花生四烯酸作为过氧化事件的特别易感靶标。质谱法将用作氧化磷脂结构表征的主要工具。将携带亲电脂质自由基产物和靶蛋白的共价加合物的结构研究，以确定加合物形成的位点和为确定共价加合物脂质部分的结构而开发的技术。将开发第二个主要重点，以确定共价加合物的脂质部分的结构。第二个主要重点是测试白三烯A4的替代途径。磷脂氧化的生物活性磷脂产物的结构表征将是一个协作项目的重点，该项目旨在表征那些可能诱导抗炎巨噬细胞表型的氧化磷脂产物。第二项协作研究将涉及刺激内皮细胞中环氧酶基因诱导的氧化磷脂产物的表征。最后，将研究一种收集人类受试者气溶胶中存在的脂质过氧化产物的方法。这种新颖的非侵入性方法将用于评估肺中的脂质过氧化事件，该事件可以通过使用质谱技术测量标记来定量。将使用这些在过期的呼吸中收集非挥发性分子的技术来进行上呼吸道，下气道和肺泡肺疾病的人类受试者的研究，并对蛛网膜过滤的特定产物进行定量。