Redox Transduction of Nitric Oxide Signaling

说明(申请人提供)：一氧化氮(.NO)通过cGMP依赖和非cGMP依赖的反应介导细胞信号传递，并产生次级氮氧化物(NOx)，通过氧化、亚硝化和硝化反应扩大NO的分子靶标范围。NO及其产物在疏水性组织间隔(如脂蛋白、膜)中的反应也传递NO信号。本研究项目集中于确定硝基脂肪酸(NO2-FA)的特定化学反应、生物分布和信号作用。目前的数据支持NO2-FA代表炎症副产物，作为炎症的适应性介质。重要的是，关于NO2-FA的结构特性和生化反应仍然缺乏知识，这是它们诱导适应性细胞信号反应的原因。一个中心假设为拟议的研究计划提供了重点：具体地说，硝基脂肪酸介导了调节新陈代谢和炎症的适应性细胞信号反应。这一假设将通过追求以下具体目标来检验：#1.合成和表征选定的硝基脂肪酸区域异构体；#2.探索硝基脂肪酸与PPAR受体结合和激活的机制；#3.确定硝基脂肪酸在代谢性疾病动物模型中的作用。这一研究计划的完成将填补我们目前对NO2-FA衍生物的层析行为、结构特征、反应活性以及随后的体外和体内信号作用的了解的空白，从而更好地指导设计更有效的代谢和炎症信号调节剂。与公共健康相关：这项拟议的研究计划调查由脂肪酸硝化衍生的一类新的信号媒介的化学、生物学和药理学。这些物种具有临床意义的信号作用将通过确定它们独特而有效地激活核脂受体过氧化体增殖物激活受体-3(PPAR3)的基础来探索，PPAR3至少由这类信号介质的一个方面显示。总体而言，这项创新的拟议研究的成功完成为与衰老相关的疾病的治疗带来了令人兴奋的新希望，如动脉硬化、高血压和糖尿病。

DESCRIPTION (provided by applicant): 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 in hydrophobic tissue compartments (e.g., lipoproteins, membranes) also transduce .NO signaling. This research project focuses on identifying the specific chemical reactivities, biodistribution and signaling actions of nitrated fatty acids (generically termed "NO2-FA"). Current data support that NO2-FA represent inflammatory byproducts that serve as adaptive mediators of inflammation. Importantly, there remains a lack of knowledge regarding the structural properties and biochemical reactivities of NO2-FA that account for their induction of adaptive cell signaling responses. A central hypothesis provides focus to the proposed research plan: specifically, that nitro-fatty acids mediate adaptive cell signaling reactions that regulate metabolism and inflammation. This hypothesis will be tested by pursuing the following Specific Aims: #1. Synthesize and characterize selected nitro-fatty acid regioisomers; #2. Explore the mechanisms of PPAR receptor binding and activation by nitro-fatty acids; #3. Define the actions of nitro-fatty acids in an animal model of metabolic disease. Accomplishment of this research plan will fill the void in our current understanding of the chromatographic behavior, structural characteristics, reactivity and consequent in vitro and in vivo signaling actions of NO2-FA derivatives, thus better guiding the design of more efficacious pharmacologic modulators of metabolic and inflammatory signaling. PUBLIC HEALTH RELEVANCE: This proposed research plan investigates the chemical biology and pharmacology of a new class of signaling mediators derived by the nitration of fatty acids. Clinically-significant signaling actions of these species will be explored by defining the basis for their unique and potent activation of the nuclear lipid receptor peroxisome proliferator activating receptor-3 (PPAR3) that is displayed by at least one facet of this class of signaling mediators. Overall, successful accomplishment of this innovative proposed study holds exciting new promise for the treatment of diseases associated with aging, such as arteriosclerosis, hypertension and diabetes.