Redox Transduction of Nitric Oxide Signaling

一氧化氮信号传导的氧化还原转导

基本信息

批准号：
7843487
负责人：
Bruce Alan Freeman
金额：
$ 50.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7843487
关键词：
2,4-thiazolidinedione Accounting Address Adipose tissue Aging Animal Model Arteriosclerosis Behavior Biochemical Biodistribution Biological Biological Assay Biology Body Weight Bone Density CD36 gene Carbon Cell Signaling Process Characteristics Chemicals Cyclic GMP Data Diabetes Mellitus Diabetic Diet Diet Disease Dual-Energy X-Ray Absorptiometry Environment Event Fatty Acids Fatty acid glycerol esters Foundations Free Radicals Gene Expression Gene Expression Regulation Genes Goals Guanylate Cyclase Hyperglycemia Hyperinsulinism Hyperlipidemia Hypertension In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Insulin Insulin Resistance Knowledge Leptin Ligands Linoleic Acids Lipids Lipoproteins Measurement Mediating Mediator of activation protein Membrane Metabolic Metabolic Diseases Metabolism Modeling Molecular Molecular Conformation Molecular Target Mus Nitrates Nitric Oxide Nitrogen Oxides Nitrosation Nonesterified Fatty Acids Nuclear Oleic Acids Organ Oxidation-Reduction Oxygen Pattern Peroxisome Proliferator-Activated Receptors Pharmacology Plasma Property Pump Radial Reaction Reagent Regulation Research Research Project Grants Scanning Signal Transduction Solid Stearic Acids Structure-Activity Relationship Sulfhydryl Compounds Testing Thiazolidinediones Tissues Treatment Efficacy Triglycerides Unsaturated Fatty Acids Vertebral column Weight Gain Wild Type Mouse adiponectin base clinically significant design feeding genetic regulatory protein glucose tolerance in vivo indexing innovation lipid biosynthesis lipophilicity nitration novel oxidation physical property public health relevance receptor receptor binding receptor expression response rosiglitazone

项目摘要

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.

描述（由申请人提供）：一氧化氮（.NO）通过CGMP和非CGMP依赖性反应介导细胞信号传导，并产生氮（NOX）的二级氧化物，这些氧化物（NOX）通过氧化，硝化，硝化和硝化反应扩大了.NO的分子靶标。 .NO及其产物在疏水组织室（例如脂蛋白，膜）中的反应也会传递。该研究项目着重于识别硝酸脂肪酸的特定化学反应性，生物分布和信号传导作用（通常称为“ NO2-FA”）。当前的数据支持NO2-FA代表炎症副产品，这些副产品是炎症的适应性介体。重要的是，关于NO2-FA的结构特性和生化反应性仍然缺乏知识，这解释了它们诱导自适应细胞信号反应。中央假设将重点放在拟议的研究计划上：具体而言，硝基脂肪酸介导调节代谢和炎症的适应性细胞信号反应。该假设将通过追求以下特定目的来检验：＃1。合成并表征选定的硝基脂肪酸酸性分散剂；＃2。探索硝基脂肪酸的PPA受体结合和激活的机制；＃3。定义硝基脂肪酸在代谢疾病动物模型中的作用。该研究计划的完成将填补我们当前对NO2-FA衍生物的体外和体外和体内信号传导作用的理解，从而更好地指导代谢性和炎症信号传导的更有效的药理调节剂的设计。公共卫生相关性：该拟议的研究计划调查了通过脂肪酸硝化衍生的新的信号传导介质的化学生物学和药理学。这些物种的临床信号传导作用将通过定义其独特而有效激活的基础，其核脂质受体过氧化物酶体增殖物激活受体-3（PPAR3）至少由这类信号介体的一个方面显示。总体而言，这项创新拟议的研究的成功完成为治疗与衰老相关的疾病（例如动脉硬化，高血压和糖尿病）提供了令人兴奋的新希望。