MECHANISTIC STUDIES OF OXYGEN PATHOLOGY

分子氧（O2）衍生的氧化物质是氧化反应的主要参与者。 引发和传播许多哺乳动物疾病。 分子的作用 氧化剂在疾病中心周围的细胞功能损伤 膜通过启动脂质过氧化，因此，一个合理的 预防性治疗干预的方法可以基于 控制这个启动过程。 不幸的是入会过程 是脂质过氧化作用中最不为人所知的机制。 这 建议旨在提供一个详细的机制描述脂质 在模型膜（脂质体）中的过氧化起始作为一个必要的 为今后在体内研究这一过程奠定了基础。 工作 假设脂质过氧化作用的启动机制是 氧化剂和环境依赖性。 具体实验目标如下： 如下 首先，生物学上重要的氧化剂将被评估为 它们在化学定义的环境中引发脂质过氧化的能力 含有氧化剂所必需的结构元素的脂质体 易感性 该评估将定义化学和 环境（即：发电地点）的不同要求 氧化剂 其次，将对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， 评价脂质过氧化增敏和氧化剂的差异 由于这些活性物质的存在而产生的影响。 三是 将确定所有氧化剂的引发机制， 诱导未过氧化和过氧化的脂质过氧化 脂质体。 不同的引发机制之间的比较 氧化剂应允许适用于代谢物测定的建议， 生物活性氧化剂的来源和身份。 初步结果已经确定了一个核心作用的过羟基 自由基，生物上最普遍存在的氧的共轭酸 种，超氧化物，在脂质过氧化反应的启动。 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 过氧化作用 初步结果使一个假设的 过羟基自由基和脂质过氧化氢的协同作用 心脏病，胃病和各种作用机制 毒品 因此，预计这些研究的结果将公开 用于设计和实施治疗的各种途径 氧化剂诱导的疾病状态的干预-这一长期目标 研究计划。

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.