Anti-Inflammatory Lipid Mediators in Asthma

哮喘中的抗炎脂质介质

基本信息

批准号：
9769851
负责人：
Bruce Alan Freeman
金额：
$ 74.34万
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：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769851
关键词：
Acids Affect Alkylation Amino Acids Anti-inflammatory Asthma Bacteria Biochemical Biological Models Blinded Cell physiology Cells Chemicals Chronic Clinical Clinical Research Complement Complex Cross-Over Studies Crossover Design Cyclic GMP Cysteine Data Diet Digestion Drug Kinetics Enzymes Evaluation Expression Profiling FDA approved Fatty Acids Fatty acid glycerol esters Formulation Gene Expression Gene Expression Profile Generations Home environment Homeostasis Human Hyperactive behavior Hypertension Impairment Incidence Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Inflammatory Response Pathway Link Lung Mediating Mediator of activation protein Medical Metabolic Metabolic syndrome Metabolism Metalloproteins Molecular Weight Mus Nature Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Nitrogen Dioxide Nitrogen Oxides Nitrosation Obese Mice Obesity Oils Oral Organ Oxidation-Reduction Oxides Oxygen PPAR gamma Pathogenicity Pharmaceutical Preparations Pharmacology Phenotype Physiological Placebos Plants Population Post-Translational Protein Processing Proteins Proteome Pulmonary Inflammation Reaction Research Risk Salivary Signal Transduction Site Structure Structure of parenchyma of lung Sulfhydryl Compounds Testing Therapeutic Time Tissues Toxicology Transcription Regulatory Protein Unsaturated Fatty Acids adduct adipokines airway hyperresponsiveness airway inflammation asthmatic asthmatic patient attenuation cytokine design dietary constituent drug candidate genotoxicity in vivo inflammatory milieu insulin sensitivity lipid mediator microbiome mouse model nitration nitroalkene novel therapeutics oxidation phase 1 study phase 1 testing phase 2 designs pre-clinical protein structure function public health relevance receptor response restoration transcription factor volunteer

项目摘要

DESCRIPTION (provided by applicant): Cell signaling actions mediated by reduction-oxidation (redox)-dependent post-translational modifications include the oxidation, glutathionylation, S-nitrosation, and alkylation of cysteine. These reactions intimately link metabolic and inflammatory status with changes in cell and organ function, since many enzymes, receptors and transcriptional regulatory proteins mediating metabolic and inflammatory responses contain functionally- significant hyperactive cysteine thiols. Particular focus is being placed on reaction mediated by nitric oxide (NO), nitrite (NO2-) and nitrate (NO3-) and secondary nitrogen oxides and the unique redox signaling responses they induce via fatty acid nitration reactions. The nature and amounts of various nitrogen oxides generated endogenously are dependent on inflammatory status, diet, acidic microenvironments and NO3--reducing enter salivary bacterial populations. Many of these products are chemically-reactive and generate protein NO- home complexes, protein Cys-NO adducts (RSNO) and in the research plan, electrophilic fatty acid nitroalkenes (NO2-FA) that readily and reversibly alkylate susceptible protein thiols. The cGMP-independent pleiotropic signaling actions of NO2-FAs induce adaptive tissue responses that include beneficial shifts in adipokine and cytokine expression, restoration of insulin sensitivity and the attenuation of airway hyperactivity. This motivated us to hypothesize that the promotion of nitro-fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary complications. To test this concept, a de- risked drug strategy will be evaluated by pursuing both mechanistically-revealing model system studies and a blinded crossover design Phase 2 clinical study: Aim #1 - Identify the sites of NO2-FA adduction in the lung tissue of obese mice with airway hyperactivity and define the biochemical and physiological responses to oral NO2-FA administration. Aim #2 - Evaluate the clinical responses of obese asthmatic patients to the orally-administered NO2-FA, 10-nitro-octadeca-9-enoic acid (NO2-OA). We will identify key sites of NO2-FA-induced PTMs in the lungs of obese mice with airway hyperactivity (AHR) and define how this affects redox-sensitive transcription factor (TF) function, gene expression profiles and activities of critical enzyme targets. Current data support that NO2-FA-mediated PTMs promote salutary responses in murine models of pulmonary inflammation and AHR. Both IV and oral formulations of NO2-FA have undergone extensive preclinical toxicology and pharmacokinetics evaluation and are in FDA-approved Phase 1 testing in humans. The physiological and biochemical responses of obese asthmatics to NO2-FA will be studied in a blinded, placebo-controlled crossover study. These responses to NO2-FA are anticipated to be more efficacious than many single-target asthma drugs, because the pleiotropic anti-inflammatory signaling actions of NO2-FA are expected to strike a pharmacological chord, rather than a note, in this complex inflammatory phenotype.

描述（由适用提供）：通过还原氧化（氧化还原）依赖性的翻译后修饰介导的细胞信号传导作用包括氧化，谷胱甘肽化，S-硝化和半胱氨酸的酒精化。这些反应将代谢和炎症状态与细胞和器官功能的变化紧密联系起来，因为许多介导代谢反应的酶，受体和转录调节蛋白都包含功能上显着的多活跃性半胱氨酸硫醇。特别的重点是由一氧化氮（NO），亚硝酸盐（NO2-）和硝酸盐（NO3-）和二级氮氧化物以及它们通过脂肪酸硝化反应诱导的独特氧化还原信号反应所介导的反应。内源性产生的各种氮氧化物的性质和数量取决于炎症状态，饮食，酸性微环境和NO3（还原） - 还原进入唾液细菌种群。这些产品中的许多具有化学反应性，并且产生了蛋白质的无家可种，蛋白质Cys-NO加合物（RSNO），在研究计划中，电动脂肪酸硝基烷烯（NO2-FA）很容易且易反烷基烷基化易感性蛋白质硫醇。 NO2-FAS的非依赖性多效性信号传导作用诱导了适应性组织反应，包括脂肪因子和细胞因子表达的有益转移，胰岛素敏感性的恢复以及气道多动的衰减。这促使我们假设促进硝基脂肪酸信号传导减轻了代谢综合征诱导的高血压及其肺并发症。为了检验这一概念，将通过进行机械远程浏览模型系统研究和盲目的跨界设计阶段2临床研究来评估一种风险的药物策略：目标＃1-确定肥胖小鼠的肺组织中采用NO2-FA的地点，该部位具有空气多动力，并定义了生物化学和物理响应对Oral No2-Fa的管理。 AIM＃2-评估肥胖哮喘患者对口服的NO2-FA，10-硝基-Octadeca-9-烯酸（NO2-OA）的临床反应。我们将确定具有气道多动症（AHR）的肥胖小鼠肺NO2-FA诱导的PTM的关键部位，并定义这如何影响氧化还原敏感的转录因子（TF）功能，关键酶靶标的基因表达谱和活性。当前的数据支持NO2-FA介导的PTM促进了肺部感染和AHR的鼠模型中的有益反应。 NO2-FA的IV和口服公式都经历了广泛的临床前毒理学和药代动力学评估，并且在FDA批准的人类中进行了1阶段测试。肥胖哮喘患者对NO2-FA的物理和生化反应将在一项盲目的安慰剂对照跨界研究中进行研究。这些对NO2-FA的反应预计将比许多单一目标哮喘药物更有效，因为在这种复杂的炎症表型中，NO2-FA的多效性抗炎信号传导作用有望在这种复杂的炎症表型中引起药品和弦。