MECHANISTIC STUDIES OF OXYGEN PATHOLOGY

氧病理学的机制研究

• 批准号: 3297782
• 负责人: THOMAS A DIX
• 金额: $ 10.13万
• 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/3297782
• 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.

氧(O2)衍生的氧化物种是 许多哺乳动物疾病的起源和传播。分子作用 氧化剂在疾病中心围绕细胞功能损害 通过引发膜脂过氧化，从而合理地 预防性治疗干预的方法可以基于 控制着这个启动过程。不幸的是，启动过程 是对脂质过氧化作用了解最少的一个方面。这 该提案旨在提供对脂类的详细机制描述 模型膜(脂质体)中的过氧化引发是必需的 为今后在体内研究这一过程奠定了基础。在工作中 假设脂质过氧化的启动机制既有 依赖于氧化剂和环境。具体的实验目标是 下面是。首先，具有生物意义的氧化剂将被评估为 它们在化学定义的条件下引发脂质过氧化的能力 含有氧化剂所需结构元素的脂质体 敏感度。这项评估将定义化学和 环境(即发电地点)要求不同 氧化剂。其次，将对脂质体进行平行评估 含有生物上合适浓度的脂质过氧化氢， 评价脂质过氧化增敏作用和差异氧化剂 由于这些活性物种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。 未过氧化和过氧化均可诱导脂质过氧化 脂质体。两种不同启动机制的比较研究 氧化剂应允许代谢物分析的建议适用于 活体生物活性氧化剂的来源和鉴定。 初步结果确定了过氧化氢的核心作用。 自由基，是生物上最普遍存在的氧的共轭酸 脂质过氧化引发的物种，超氧化物。此外，胖子 酸性过氧化氢使脂质对过氧自由基依赖的脂质敏感 过氧化。初步结果使我们能够假设 过氧化氢与脂质过氧化的协同作用 心脏病、胃病及其各种作用机制的研究进展 毒品。因此，预计这些研究的结果将会公开。 治疗方案的设计和实施的各种途径 对氧化剂诱导的疾病状态的干预--这一长期目标 研究计划。