Redox Transduction of Nitric Oxide Signaling

一氧化氮（NO）通过cGMP依赖性和非cGMP依赖性反应介导细胞信号传导， 二次氮氧化物（NOx），其通过氧化扩大NO的分子目标范围， 亚硝化和硝化反应。NO及其产物与不饱和脂肪酸的反应 通过形成亲电子硝基脂肪酸（一般称为NO2-FA）来转导NO信号传导。的 为即将更新的R37/Merit奖而设定的研究目标将继续探索这个概念 炎症衍生的亲电脂肪酸是氧化还原信号介质， 它们高度保守的分子靶（例如，转录调节蛋白）来调节适应性细胞 信号事件。这些反应使生物体能够将基因表达与它们的代谢， 环境和炎症状态。重要的是，仍然缺乏关于 NO2-FA诱导适应性细胞结构特性和生化反应性 信号响应。我们将利用HPLC-MS/MS来表征EFOX的模式和机制 在与肥胖诱导的糖尿病相关的条件下产生。在了解了更多关于结构 特征，浓度，代谢和特定EFOX的分子靶点，我们将评估 通过在环境中给予这些物种，关键EFOX的合成同系物的治疗潜力 肥胖诱导的糖尿病模型，高脂肪饮食喂养的C57/BI 6小鼠。据推测，亲电 由氧化炎症环境形成的不饱和脂肪酸衍生物介导适应性细胞 信号响应。这一假设将通过追求三个具体目标来检验：1。结构上 表征并定量炎性细胞中存在的主要亲电脂肪酸种类， 肥胖的环境，使用细胞，啮齿动物和临床来源的标本。2.定义贡献 线粒体氧化还原反应中的不饱和脂肪酸的亲电衍生物的形成。 3.在肥胖诱导的细胞和动物模型中检查亲电脂肪酸的抗炎作用 糖尿病

Nitric oxide (NO) mediates cell signaling via cGMP- and non-cGMP-dependent reactions and yields secondary oxides of nitrogen (NOx) that expand the range of molecular targets of NO via oxidation, nitrosation and nitration reactions. The reactions of NO and its products with unsaturated fatty acids transduces NO signaling via the formation of electrophilic nitro-fatty acids, generically termed N02-FA. The research objectives set for the upcoming renewal of this R37/Merit award will continue to probe the concept that inflammatory-derived electrophilic fatty acids are redox signaling mediators that work in tandem with their highly conserved molecular targets (e.g., transcriptional regulatory proteins) to regulate adaptive cell signaling events. These reactions permit organisms to link gene expression with their metabolic, environmental and inflammatory status. Importantly, there still remains a lack of knowledge regarding the structural properties and biochemical reactivities of N02-FA that account for their induction of adaptive cell signaling responses. We will utilize HPLC-MS/MS to characterize the patterns and mechanisms of EFOX production during conditions relevant to obesity-induced diabetes. After learning more about the structural characteristics, concentrations, metabolism and molecular targets of specific EFOXs, we will evaluate the therapeutic potential of synthetic homologs of key EFOXs by administering these species in the setting of a model of obesity-induced diabetes, high fat diet-fed C57/BI6 mice. It is hypothesized that the electrophilic derivatives of unsaturated fatty acids formed by the oxidative inflammatory milieu mediate adaptive cell signaling responses. This hypothesis will be tested by pursuing three Specific Aims: 1. Structurally characterize and quantitate the predominant electrophilic fatty acid species present in the inflammatory milieu of obesity, using cell, rodent and clinically-derived specimens. 2. Define the contribution of mitochondrial redox reactions in the formation of electrophilic derivatives of unsaturated fatty acids. 3. Examine the anti-inflammatory actions of electrophilic fatty acids in cell and animal models of obesityinduced diabetes.