PATHWAYS TO 4-HYDROXYNONENAL

4-羟基壬烯醛的途径

• 批准号: 7209629
• 负责人: ALAN R. BRASH
• 金额: $ 15.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209629
• 关键词: adduct; aldehydes; ascorbate; eicosanoid metabolism; eicosanoids; epoxides; high performance liquid chromatography; human tissue; intermolecular interaction; laboratory mouse; lipids; mass spectrometry; nuclear magnetic resonance spectroscopy; oxidation; oxidative stress; pharmacology; stable isotope double label; toxicology

The long-term objective of this project is to elucidate the basis of aldehyde formation during lipid peroxidation, and thus advance our understanding of the etiology of atherogenesis and other diseases associated with oxidative stress. 4-Hydroxy-nonenal (HNE) and related aldehydes are among the most important reactive agents formed from polyunsaturated fatty acids during autoxidation yet the reactions underlying their synthesis are not at all well understood. We have now developed a detailed hypothesis implicating inter-molecular peroxyl radical reactions as a main pathway leading to HNE and related aldehydes. This is associated with cross-molecular epoxidations that can generate additional novel and bioactive products. The proposed mechanisms will be examined utilizing identification of intermediates by HPLC, UV, mass spectrometry, and NMR, and using stable isotope labeling to follow the reaction pathway and study the mechanisms of oxygen transfer. The Specific Aims are to investigate: 1. Inter-molecular mechanisms of 4-hydroperoxy-nonenal formation: peroxyl radical-dependent pathways 2. Aldehyde and epoxide formation during autoxidation of natural substrates 3. Biological implications of novel lipid peroxidation-derived products An important component of these studies in Aims 1 and 2 is the proposed isolation of individual species of cross-linked fatty acids and phospholipids, their precise structural and stereochemical characterization, and a detailed analysis of their degradative products, postulated to include the HNE-related aldehydes. The activity of novel epoxy-hydroperoxide products of lipid peroxidation will be assessed as PPAR ligands, and vitamin C-HNE adducts will be characterized and quantified (Aim 3). Elucidation of the biosynthesis of these reactive aldehydes has practical applications in defining the parameters that influence the production of aldehydes, identification of novel and reactive chemical species involved in the synthetic pathways, and improving the assessment of peroxide tone/oxidative stress in tissues.

本项目的长期目标是阐明脂质代谢过程中醛形成的基础。 过氧化作用，从而促进我们对动脉粥样硬化和其他疾病的病因学的理解 与氧化应激有关。4-羟基壬烯醛（HNE）和相关醛类是最常见的醛类化合物之一。 在自氧化过程中由多不饱和脂肪酸形成的重要反应剂 其合成的根本原因还没有得到很好的理解。我们现在提出了一个详细的假设 暗示分子间过氧自由基反应是导致HNE和相关的 醛类。这与跨分子环氧化有关，该环氧化可以产生额外的新的和 生物活性产品。将通过以下方法鉴定中间体来检查拟定的机制： HPLC、UV、质谱和NMR，并使用稳定同位素标记来追踪反应途径 并研究氧气传输的机制。具体目标是调查： 1. 4-过氧壬烯醛形成的分子间机理：过氧自由基依赖的途径 2.天然底物自氧化过程中醛和环氧化物的形成 3.新型脂质过氧化产物的生物学意义 目标1和目标2中这些研究的一个重要组成部分是提议的分离单个物种， 交联脂肪酸和磷脂，其精确的结构和立体化学表征，以及 对其降解产物进行了详细分析，假定包括HNE相关醛。的 脂质过氧化的新型环氧-氢过氧化物产物的活性将作为PPAR配体进行评估， 将对维生素C-HNE加合物进行表征和定量（目标3）。 这些反应性醛的生物合成的阐明在定义生物合成中具有实际应用。 影响醛生产的参数，新的和反应性化学物质的鉴定 参与合成途径，并改善过氧化物张力/氧化应激的评估， 组织中