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(摘自《调查者摘要》)：一氧化氮(NO)是一种 许多哺乳动物细胞产生的强有力的介体。没有人经历过无数次 产生几种氧化还原形式的反应。NO可以作为一种细胞信号 分子，作为一种有害物种，或作为抗氧化剂。这取决于 浓度、暴露持续时间以及与其接触的目标 互动。在细胞靶标中，细胞硫醇的修饰一直是 被证明是NO氧化还原形式的重要信号机制。这可能会导致 以S-亚硝基-谷胱甘肽或蛋白质-S-亚硝化。这些 细胞硫醇的修饰可以被认为是一种“开启”的信号。这 该提案将重点放在反向NO介导的硫醇修饰上，作为一种潜在的“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，这是已知的 通过谷氧还蛋白和谷胱甘肽的联合活性有效地降低 氧化还原循环。申请人提出，该机制是关闭信号。AS 这样，GSH氧化还原循环可能通过同样的方式起到保护作用。 机制。该提案的目标是调查 NO、细胞硫醇与GHS氧化还原循环的相互作用 暴露于外源性NO供体的内皮细胞或其中NO 内生的，内生的总体假设是GSH氧化还原循环 通过与NO相关物种直接相互作用来调节NO介导的信号转导 并通过逆转涉及蛋白质的蛋白质硫醇修饰机制 二硫化物的形成。假设类似的机制保护细胞不受 NO的破坏性影响。