Redox Transduction of Nitric Oxide Signaling

描述（由申请人提供）：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，并产生二次氮氧化物（NOx），扩大分子靶标范围。一氧化氮通过氧化、亚硝化和硝化反应产生。的反应。NO及其在疏水组织腔室中的产物（如脂蛋白、膜）也可进行转导。没有信号。本研究项目的重点是鉴定硝化脂肪酸（一般称为NO2-FA）的特定化学反应活性、生物分布和信号传导作用。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诱导适应性细胞信号反应的结构特性和生化反应的知识仍然缺乏。一个中心假设为提出的研究计划提供了重点：具体来说，硝基脂肪酸介导调节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验证：合成和表征选定的硝基脂肪酸区域异构体；# 2。探讨硝基脂肪酸对PPAR受体的作用机制；# 3。确定硝基脂肪酸在代谢性疾病动物模型中的作用。本研究计划的完成将填补我们目前对NO2-FA衍生物的色谱行为、结构特征、反应性及其在体外和体内信号作用的认识空白，从而更好地指导设计更有效的代谢和炎症信号的药理调节剂。公共卫生相关性：本研究计划研究一类由脂肪酸硝化衍生的新型信号介质的化学生物学和药理学。通过定义核脂质受体过氧化物酶体增殖体激活受体-3 （PPAR3）的独特和有效激活的基础，这些物种的临床重要信号传导作用将被探索，这类信号传导介质的至少一个方面表现出来。总的来说，这项创新研究的成功完成为动脉硬化、高血压和糖尿病等与衰老相关的疾病的治疗带来了令人兴奋的新希望。

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.