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.

二恶英（O2）衍生的氧化物种是主要参与者 许多哺乳动物疾病的启动和传播。 分子作用 疾病中心的氧化剂围绕细胞功能障碍 膜通过脂质过氧化的启动，因此有理 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 是脂质过氧化的最低理解的方面。 这 建议旨在提供脂质的详细机械描述 模型膜（脂质体）中的过氧化启动作为必不可少的 该过程在体内的未来研究基础。 工作 假设是脂质过氧化启动的机理都是 氧化剂和环境依赖性。 具体的实验目标是 跟随。 首先，将对生物学意义的氧化剂评估为 具有化学定义的脂质过氧化的能力 含有氧化剂必要的结构元素的脂质体 敏感性。 该评估将定义化学和 环境（即发电的立场）对不同的要求 氧化剂。 其次，将用脂质体进行平行评估 含有生物学上适当的脂质氢过氧化物， 评估脂质过氧化敏化和差异氧化剂 由于存在这些反应性物种而产生的影响。 第三， 将确定所有活性氧化剂的启动机制 在未渗透和过氧化的脂质过氧化中诱导脂质过氧化 脂质体。 不同的启动机制之间的比较 氧化剂应允许提出适用于 体内生物活性氧化剂的来源和身份。 初步结果定义了旁羟基的核心作用 自由基，生物泛氧的结合酸 物种，超氧化物，脂质过氧化启动。 另外，脂肪 酸氢过氧化物使脂质敏感到丙酰基自由基依赖性脂质 过氧化。 初步结果使得 旁羟基自由基和脂质氢过氧化物的协同作用 心脏病，胃病和各种作用机理 毒品。 因此，预计这些研究的结果将开放 设计和实施治疗的各种途径 氧化剂引起的疾病状态的干预 - 这是长期目标 研究计划。