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: 2907116
• 负责人: A RICHARD WHORTON
• 金额: $ 23.49万
• 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/2907116
• 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（改编自研究者摘要）：一氧化氮 (NO) 是一种 许多哺乳动物细胞产生的有效介质。 NO经历了无数 反应产生多种氧化还原形式。 NO 可以充当细胞信号传导 分子，作为破坏性物种，或作为抗氧化剂。这取决于 浓度、暴露持续时间以及针对哪些目标 相互作用。在细胞靶标中，细胞硫醇的修饰已被 已被证明是 NO 氧化还原形式的重要信号传导机制。这可能会导致 S-亚硝基谷胱甘肽形成或蛋白质 S-亚硝基化。这些 细胞硫醇的修饰可以被认为是“开启”信号。这 提案重点关注反向 NO 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的NO修饰 硫醇导致蛋白质混合二硫化物的形成，已知 谷氧还蛋白和谷胱甘肽的联合活性可有效降低 氧化还原循环。申请人提出该机制是关闭信号。作为 因此，GSH氧化还原循环可能通过相同的方式发挥保护作用 机制。该提案的目标是研究机制 NO、细胞硫醇和 GHS 氧化还原循环之间的相互作用 内皮细胞暴露于外源性 NO 供体或含有 NO 的细胞模型 内生产生的。总体假设是 GSH 氧化还原循环 通过直接与 NO 相关物种相互作用来调节 NO 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 二硫化物的形成。假设类似的机制可以保护细胞免受 NO 的破坏作用。