MECHANISTIC STUDIES OF OXYGEN PATHOLOGY

氧病理学的机制研究

• 批准号: 3297779
• 负责人: THOMAS A DIX
• 金额: $ 10.97万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3297779
• 关键词: chemical reaction; fatty acids; free radical oxygen; high performance liquid chromatography; lipid bilayer membrane; lipid peroxides; liposomes; membrane structure; oxidizing agents; oxygen; radiotracer; solutions; superoxides

Dioxygen (O2)-derived oxidizing species are major participants in the initiation and propagation of many mammalian diseases. The molecular role of oxidants in disease centers around functional impairment of cell membranes through the initiation of lipid peroxidation, thus a rational approach towards preventative therapeutic intervention can be based on controlling this initiation process. Unfortunately, the initiation process is the least mechanistically understood aspect of lipid peroxidation. This proposal is designed to provide a detailed mechanistic description of lipid peroxidation initiation in model membranes (liposomes) as an essential foundation for the future study of this process in vivo. The working hypothesis is that the mechanism of lipid peroxidation initiation is both oxidant- and environment-dependent. Specific experimental goals are as follows. First, the biologically significant oxidants will be evaluated as to their ability to initiate lipid peroxidation in chemically defined liposomes containing the necessary structural elements for oxidant susceptibility. This evaluation will define both chemical and environmental (i.e.-location of generation) requirements for the different oxidants. Second, a parallel evaluation will be preformed with liposomes containing biologically appropriate concentrations of lipid hydroperoxides, to evaluate lipid peroxidation sensitization and differential oxidant effects due to the presence of these reactive species. Third, the mechanisms of initiation will be determined for all oxidants active in inducing lipid peroxidation in both unperoxidized and peroxidized liposomes. A comparison between mechanisms of initiation of the different oxidants should allow for the proposal of metabolite assays applicable in vivo for the sources and identities of biologically active oxidants. Preliminary results have defined a central role for the perhydroxyl radical, the conjugate acid of the most biologically ubiquitous oxygen species, superoxide, in lipid peroxidation initiation. In addition, fatty acid hydroperoxides sensitize lipids to perhydroxyl radical-dependent lipid peroxidation. The preliminary results enable a postulation of the synergistic role of the perhydroxyl radical and lipid hydroperoxides in heart disease, stomach disease and the mechanism of action of various drugs. Thus, it is anticipated that the results of these studies will open various avenues for the design and implementation of therapeutic interventions of oxidant-induced disease states-the long-term goal of this research program.

分子氧 (O2) 衍生的氧化物质是该过程的主要参与者 许多哺乳动物疾病的发生和传播。 分子作用 氧化剂在疾病中的作用以细胞功能损伤为中心 通过引发脂质过氧化作用，从而合理地 预防性治疗干预的方法可以基于 控制这个启动过程。 不幸的是，启动过程 是脂质过氧化的机制上最不了解的方面。 这 该提案旨在提供脂质的详细机制描述 模型膜（脂质体）中的过氧化引发是必不可少的 为今后体内这一过程的研究奠定了基础。 工作中 假设脂质过氧化引发的机制是 氧化剂和环境依赖性。 具体实验目标如下 接下来。 首先，具有生物学意义的氧化剂将被评估为 其在化学定义中引发脂质过氧化的能力 含有氧化剂必需结构元素的脂质体 易感性。 该评估将定义化学和 不同的环境（即发电地点）要求 氧化剂。 其次，将用脂质体进行平行评价 含有生物学上适当浓度的脂质氢过氧化物， 评估脂质过氧化致敏性和差异氧化剂 由于这些活性物质的存在而产生的影响。 第三， 将确定所有活性氧化剂的引发机制 诱导未过氧化和过氧化脂质过氧化 脂质体。 不同启动机制的比较 氧化剂应考虑到适用于代谢物测定的建议 体内生物活性氧化剂的来源和特性。 初步结果确定了过羟基化合物的核心作用 自由基，生物上最普遍存在的氧的共轭酸 物种，超氧化物，在脂质过氧化引发中。 此外，脂肪 酸性氢过氧化物使脂质对过羟基自由基依赖性脂质敏感 过氧化。 初步结果可以假设 过羟基自由基和脂质氢过氧化物的协同作用 心脏病、胃病以及各种疾病的作用机制 药物。 因此，预计这些研究结果将公开 设计和实施治疗的各种途径 氧化诱导疾病状态的干预——本研究的长期目标 研究计划。