LIMA: Lipid anti-Inflammatory Mediators in Asthma to reduce airway hyperresponsiveness in obese asthmatics

LIMA：哮喘中的脂质抗炎介质可减少肥胖哮喘患者的气道高反应性

基本信息

批准号：
10369934
负责人：
Stacy Lynn Gelhaus
金额：
$ 74.16万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369934
关键词：
16S ribosomal RNA sequencing Acids Adult Airway Disease Anti-Inflammatory Agents Asthma Basic Science Biochemical Biological Biological Markers Blinded Body mass index Bronchial Hyperreactivity Bronchoalveolar Lavage Bronchodilator Agents Cells Chronic Clinical Clinical Research Cross-Over Studies Crossover Design Data Disease Drug Kinetics Enzymes Evaluation Fatty Acids Fatty acid glycerol esters Feces Functional disorder Gene Expression Gene Expression Profiling Generations Genome Homologous Gene Human Immune response Impact evaluation Impairment Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Response Institutional Review Boards Lipids Lung Mediating Mediator of activation protein Metabolic Metabolic syndrome Metabolism Nasal Epithelium Nitrogen Dioxide Nitrogen Oxides Nose Obesity Oral Oral Administration Oxidation-Reduction Oxides Oxygen Pathogenicity Patients Pharmaceutical Preparations Pharmacology Phase II Clinical Trials Phenotype Placebo Control Plasma Population Post-Translational Protein Processing Publishing Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Inflammation Questionnaires Reaction Research Research Design Resistance Resources Risk Rodent Safety Sampling Signal Transduction Study Subject Symptoms Testing Therapeutic Effect Toxicology Translational Research Unsaturated Fatty Acids Urine Work adipokines airway hyperresponsiveness allergic airway disease asthmatic asthmatic patient bronchial epithelium clinical phenotype cytokine design drug candidate dysbiosis gut-lung axis host microbiota improved insulin sensitivity lipid mediator metabolic profile metabolomics metatranscriptomics methacholine microbial microbiome mouse model nitration nitroalkene novel novel drug class obese person obesity treatment obesity-associated asthma phase 2 designs phase 2 testing pre-clinical primary outcome pulmonary function receptor response secondary outcome tool transcription factor transcriptome sequencing volunteer whole genome

项目摘要

Abstract. Obesity induces a chronic systemic inflammatory state characterized by impaired adipokine signaling, increased pro-inflammatory cytokine expression, inflammatory cell activation, enhanced generation of oxidizing species and pathogenic shifts in metabolic intermediates and microbial profiles. This impacts pulmonary function and increases the incidence of asthma and its exacerbations that are resistant to conventional asthma therapies. Unsaturated fatty acid nitration products (NO2-FA), generated by metabolic and inflammatory reactions, can orchestrate diverse adaptive signaling responses. When administered as pure synthetic homologs, NO2-FA mediate post-translational protein modifications that modulate activities of multiple enzymes, receptors and transcription factors regulating metabolism and inflammation. Oral administration of synthetic NO2-FA 10-nitro- octadec-9-cis-enoic acid (termed NO2-OA or CXA-10) is a safe, novel pleiotropic drug candidate that is a synthetic homolog of an endogenous mediator. In murine models of metabolic syndrome, obesity-associated allergic airway disease and pulmonary inflammation affirms that CXA-10 induces anti-inflammatory responses and normalizes airway function. We will evaluate the promising pharmacology of this new drug class via Phase 2 evaluation of the therapeutic effects of CXA-10 in subjects with late onset obesity-associated asthma. We will a) define changes in pre bronchodilator FEV1, asthma control, and methacholine responsiveness following daily oral CXA-10 administration to obese subjects (BMI >30) having airway hyperreactivity, via a blinded, placebo- controlled, double cross-over study design and b) evaluate the impact of CXA-10 administration on study subject nasal and pulmonary airway cell gene expression, urine, plasma and bronchoalveolar lavage inflammatory biomarkers and gut-lung axis microbiome responses. These mechanistic studies will reveal how CXA-10 directs the electrophilic NO2-FA-sensitive genome and microbiome to modulate systemic and airway metabolic and inflammatory intermediates that contribute to the obese asthmatic phenotype. We hypothesize that nitro-fatty acid-induced signaling and metabolic responses will improve lung function, asthma control and alleviate obesity-related airway hyperreactivity. To test this hypothesis, Aim #1 evaluates the clinical responses of obesity-associated asthma patients to the orally-administered nitro-fatty acid, CXA-10 and Aim #2 identifies the downstream host and microbial gene expression and metabolic responses of subjects before and after oral CXA-10 administration. Current data encourages that, in the setting of obesity, CXA-10 will limit lung dysfunction, promote adaptive signaling responses and shift gut bacterial populations and metabolic intermediates so as to beneficially impact the gut-lung axis.

抽象的。肥胖会诱导慢性全身性炎症状态，其特征是脂肪因子信号受损，促炎性细胞因子表达，炎症细胞激活，氧化的产生增强代谢中间体和微生物特征的物种和致病性转移。这会影响肺功能并增加了对常规哮喘疗法有抵抗力的哮喘发病率及其加剧的发生率。由代谢和炎症反应产生的不饱和脂肪酸硝酸化产物（NO2-FA）可以编排各种自适应信号反应。当用作纯合成同源物时，NO2-FA 介导翻译后蛋白质修饰，以调节多种酶，受体和调节代谢和炎症的转录因子。口服合成NO2-FA 10-硝基 - Octadec-9-Cis-烯酸（称为NO2-OA或CXA-10）是一种安全的新型多效药物候选者，是一个内源介质的合成同源物。在代谢综合征的鼠模型中，肥胖相关过敏性气道疾病和肺部炎症确认CXA-10诱导抗炎反应并规范气道功能。我们将通过阶段评估该新药物的有希望的药理学 2评估CXA-10对肥胖相关哮喘的受试者的治疗作用。我们将 a）定义支气管扩张剂FEV1，哮喘控制和甲基苯胺反应的变化口服CXA-10给肥胖受试者（BMI> 30），通过盲，安慰剂 - 受控的，双重交叉研究设计和b）评估CXA-10给药对研究主题的影响鼻和肺气道细胞基因表达，尿液，血浆和支气管腔灌洗炎症生物标志物和肠肺轴微生物组响应。这些机械研究将揭示CXA-10如何指导对无亲电NO2-FA敏感基因组和微生物组调节全身和气道代谢以及有助于肥胖哮喘表型的炎症中间体。我们假设硝基脂肪酸引起的信号传导和代谢反应将改善肺功能，哮喘控制并减轻与肥胖相关的气道高反应性。为了检验这一假设，目标＃1评估了与肥胖相关的哮喘患者与口服的硝基脂肪酸，CXA-10和AIM＃2 识别下游宿主和微生物基因表达和受试者的代谢反应口服CXA-10给药前后。当前的数据鼓励，在肥胖症的情况下，CXA-10 将限制肺功能障碍，促进自适应信号反应并改变肠道细菌种群和代谢中间体以有益地影响肠肺轴。