CELLULAR REDOX CONTROL AND NITRIC OXIDE SIGNALING

细胞氧化还原控制和一氧化氮信号传导

• 批准号: 6390101
• 负责人: A RICHARD WHORTON
• 金额: $ 22.14万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390101
• 关键词: biological signal transduction; cell line; disulfide bond; electrophoresis; glutathione; high performance liquid chromatography; nitric oxide; oxidation reduction reaction; protein disulfide reductase (glutathione); protein structure; thiols; thyrotropin; tissue /cell culture; vascular endothelium

DESCRIPTION (Adapted from Investigator's Abstract): Nitric oxide (NO) is a potent mediator produced by many mammalian cells. NO undergoes numerous reactions producing several redox forms. NO can act as a cellular signaling molecule, as a damaging species, or as an antioxidant. This depends on concentration, duration of exposure, and on which targets with which it interacts. Among cellular targets, modification of cellular thiols has been shown to be an important signaling mechanism for NO redox forms. This may lead to S-nitrosoglutathione formation or to protein S-nitrosylation. These modifications of cellular thiols can be considered an "on" signal. This proposal focuses on reverse NO-mediated thiol modification as a potential "off" signal. Preliminary experiments have found that NO modification of protein thiols leads to formation of protein mixed disulfides, which are known to be effectively reduced by the combined activities of glutaredoxin and the GSH redox cycle. The applicant proposes that this mechanism is the off signal. As such, the GSH redox cycle may play a protective role through the same mechanism. The goals of the proposal are to investigate mechanisms for interaction between NO, cellular thiols and the GHS redox cycle using endothelial cells exposed to exogenous NO donors or cell models in which NO is produced endogenously. The overall hypothesis is that the GSH redox cycle regulates NO mediated signaling by interacting directly with NO related species and by reversing protein thiol modification mechanisms involving protein disulfide formation. It is assumed that similar mechanisms protect cells from the damaging effects of NO.

描述（根据研究者的摘要进行了改编）：一氧化氮（NO）是 许多哺乳动物细胞产生的有效介质。没有很多 产生几种氧化还原形式的反应。没有可以充当蜂窝信号 分子，作为破坏性物种或抗氧化剂。这取决于 浓度，暴露持续时间以及其目标 互动。在细胞靶标中，细胞硫醇的修饰已经 被证明是无氧化还原形式的重要信号机制。这可能会导致 进行S-硝基谷硫硫代形成或蛋白S-硝基化。这些 细胞硫醇的修饰可以视为“ ON”信号。这 提案的重点是反向无介导的硫醇修饰作为潜在的“关闭” 信号。初步实验发现蛋白质没有修饰 硫醇会导致蛋白质混合二硫化物的形成，已知是 有效地通过谷歌蛋白和GSH的联合活性降低了 氧化还原周期。申请人提出这种机制是关闭信号。作为 这样，GSH氧化还原周期可能会通过相同的保护作用 机制。该提案的目标是调查针对的机制 使用NO，细胞硫醇与GHS氧化还原循环之间的相互作用 暴露于外源的NO供体或细胞模型的内皮细胞，其中NO 内源性产生。总体假设是GSH氧化还原循环 通过直接与没有相关物种的直接相互作用来调节介导的信号传导 并通过逆转涉及蛋白质的蛋白质硫醇修饰机制 二硫化形成。假定类似的机制可以保护细胞免受 NO的破坏性影响。