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: 6537477
• 负责人: A RICHARD WHORTON
• 金额: $ 22.81万
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537477
• 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强有力的介质。NO经历了许多 产生几种氧化还原形式的反应。NO可以作为细胞信号传导 分子，作为破坏性物质，或作为抗氧化剂。这取决于 浓度，暴露时间，以及与哪些目标， 互动。在细胞靶点中，细胞硫醇的修饰已经被研究。 显示为NO氧化还原形式的重要信号传导机制。这可能导致 S-亚硝基谷胱甘肽形成或蛋白质S-亚硝基化。这些 细胞硫醇的修饰可被认为是“开”信号。这 一项提案的重点是反向NO介导的巯基修饰作为潜在的“关闭” 信号了初步实验发现，NO修饰蛋白质 巯基导致形成蛋白质混合二硫化物，已知其是 谷氧还蛋白和谷胱甘肽的联合作用有效地降低了 氧化还原循环申请人提出，该机制是关闭信号。作为 因此，GSH氧化还原循环可以通过相同的方式发挥保护作用。 机制该提案的目标是调查以下机制： 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供体或细胞模型，其中NO是 是内生的。总的假设是GSH氧化还原循环 通过直接与NO相关物质相互作用调节NO介导的信号传导 通过逆转蛋白质巯基修饰机制， 二硫化物形成。假设类似的机制保护细胞免受 NO的破坏性影响。