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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：
8851643
负责人：
Bruce Alan Freeman
金额：
$ 54.41万
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：
1998
资助国家：
美国
起止时间：
1998-01-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851643
关键词：
Accounting Acute Address Amino Acids Animal Model Anti-Inflammatory Agents Anti-inflammatory Award Biochemical Blood Vessels Cell model Cells Characteristics Chemicals Chronic Clinical Clinical Research Cyclic GMP Cysteine Data Diabetes Mellitus Diet Event Fatty Acids Fatty acid glycerol esters Foundations Free Radicals Gene Expression High Pressure Liquid Chromatography Homologous Gene Inflammation Inflammation Mediators Inflammatory Inflammatory Infiltrate Inflammatory Response Ketones Knowledge Learning Link Lipids Lipoxygenase Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Target Mus NF-kappa B Nitrates Nitric Oxide Nitric Oxide Synthase Nitrogen Oxides Nitrosation Nuclear Obesity Organism Oxidants Oxidases Oxidation-Reduction Oxygenases Pattern Pharmaceutical Preparations Physiological Post-Translational Protein Processing Production Property Protein Array Proteins Publishing Reaction Research Resolution Rodent Scientist Signal Pathway Signal Transduction Signaling Protein Solid Specimen Sulfhydryl Compounds Testing Therapeutic Transcription Regulatory Protein Unsaturated Fatty Acids Vascular Diseases Work base cyclooxygenase 2 defined contribution drug discovery fatty acid oxidation feeding insight keto fatty acid nitration nitroalkene novel oxidation receptor response skills stem transcription factor

项目摘要

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.

一氧化氮（NO）通过cGMP依赖性和非cGMP依赖性反应和产率介导细胞信号传导