Redox Transduction of Nitric Oxide Signaling

一氧化氮(NO)通过cGMP依赖和非cGMP依赖的反应介导细胞信号转导 二次氮氧化物(NOx)，通过氧化扩大了NO的分子靶标范围， 亚硝化和硝化反应。NO及其产物与不饱和脂肪酸的反应 通过形成亲电硝基脂肪酸传递NO信号，通常称为N02-FA。这个 为即将续期的R37/Merit奖设定的研究目标将继续探索这一概念 炎性衍生的亲电脂肪酸是氧化还原信号媒介，与 它们高度保守的分子靶点(如转录调节蛋白)调节适应细胞 信号事件。这些反应允许有机体将基因表达与他们的新陈代谢联系起来， 环境和炎症状态。重要的是，仍然缺乏关于 N02-FA诱导适应细胞的结构特性和生化反应 信号响应。我们将利用HPLC-MS/MS来表征EFOX的模式和作用机制 在与肥胖引起的糖尿病相关的条件下生产。在了解了更多关于结构的 特定EFOX的特性、浓度、代谢和分子靶点，我们将评估 关键EFOX的合成同系物在一种情况下通过给予这些物种的治疗潜力 建立肥胖糖尿病模型，高脂饮食喂养C57/BI6小鼠。据推测，亲电性 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.在结构上 表征和定量存在于炎症中的主要亲电脂肪酸种类 肥胖环境，使用细胞、啮齿动物和临床来源的标本。2.界定 不饱和脂肪酸电子衍生物形成过程中的线粒体氧化还原反应。 3.检测亲电性脂肪酸在细胞和动物肥胖模型中的抗炎作用 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.