Reactive Intermediates of Oxidative Lipid Fragmentation

氧化脂质断裂的反应中间体

• 批准号: 7102418
• 负责人: Robert Gerd Salomon
• 金额: $ 28.68万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102418
• 关键词: conditioning; free radicals; lipids; oxidation; retina

DESCRIPTION (provided by applicant): The overall objective of the project is to provide a fundamental mechanistic basis for the rational design of therapeutic measures to prevent or ameliorate the pathological consequences of lipid oxidation, for example, by blocking the formation of certain toxic products that damage the retina resulting in age-related macular degeneration. Our immediate goal is to understand oxidative fragmentation reactions of polyunsaturated fatty acyl derivatives that generate a complex mixture of oxidatively truncated phospholipids (oxPCs) and aliphatic lipid fragments. These fragmentation products exhibit diverse and often pathological biological activities. Mutagenic epoxyalkenals and cytotoxic hydroxyalkenals are of particular interest. Knowledge of the chemistry of the reactive intermediates involved in their generation is important for understanding how environmental or genetic factors can promote their formation. Our recent observations showed that exposure to intense light generates significant levels of biologically active oxPCs in rat retinas, and demonstrated that oxPCs can be produced through non free radical pathways that involve singlet, i.e., photoexcited, oxygen. Although the generation of singlet oxygen has been suspected of having pathological significance, an understanding of the molecular basis of the consequent retinal pathology is sorely lacking. The project focuses on studying key intermediates that are not stable under the oxidative fragmentation reaction conditions. Three basic questions will be addressed: (1) are the putative intermediates actually involved, and if so (2) what products are generated by their decomposition and (3) by what mechanism(s) do they fragment? In some cases, they will be trapped as stable derivatives to confirm their involvement. To provide ample quantities of some reactive intermediates, unambiguous total syntheses will be designed and executed. The authentic samples will be used as standards for establishing methods to detect and quantify levels of the intermediates in oxidation reaction product mixtures and in vivo. Their generation and conversion into toxic or innocuous end products will then be investigated. We will determine the influences of (1) environments such as those found in different organelles or associated with pathological conditions, (2) levels of cofactors, or (3) oxidation initiating systems and inhibitors, on the production of the reactive intermediates and on the relative importance of various pathways for their subsequent transformations.

描述（由申请人提供）：该项目的总体目标是为合理设计治疗措施提供基本机制基础，以预防或改善脂质氧化的病理后果，例如，通过阻止某些有毒产物的形成，损害视网膜，导致年龄相关性黄斑变性。我们的近期目标是了解多不饱和脂肪酰基衍生物的氧化断裂反应，这些反应产生氧化截短的磷脂（oxPC）和脂肪族脂质碎片的复杂混合物。这些碎片产物表现出多种且常常是病理性的生物活性。诱变环氧烯醛和细胞毒性羟基烯醛特别令人感兴趣。了解其生成过程中涉及的反应中间体的化学性质对于理解环境或遗传因素如何促进其形成非常重要。我们最近的观察表明，暴露在强光下会在大鼠视网膜中产生显着水平的生物活性 oxPC，并证明 oxPC 可以通过涉及单线态（即光激发氧）的非自由基途径产生。尽管人们怀疑单线态氧的产生具有病理意义，但对随之而来的视网膜病理学的分子基础的了解却非常缺乏。 该项目重点研究氧化裂解反应条件下不稳定的关键中间体。将解决三个基本问题：（1）假定的中间体是否实际涉及，如果是的话（2）它们的分解产生什么产物，（3）它们通过什么机制碎裂？在某些情况下，它们会被困为稳定的衍生品以确认其参与。为了提供充足数量的一些反应中间体，将设计和执行明确的全合成。真实样品将用作建立检测和定量氧化反应产物混合物和体内中间体水平的方法的标准。然后将调查它们的产生和转化为有毒或无毒最终产品的情况。我们将确定 (1) 环境（例如在不同细胞器中发现的或与病理条件相关的环境）、(2) 辅因子水平或 (3) 氧化引发系统和抑制剂对反应中间体的产生和对反应中间体的影响。各种途径对其后续转化的相对重要性。