Mitochondrial Redox Perturbations in Obese Allergic Asthma

肥胖过敏性哮喘中的线粒体氧化还原扰动

基本信息

批准号：
10013286
负责人：
Vikas Anathy
金额：
$ 76.77万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-07 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013286
关键词：
Address Allergens Allergic Allergic inflammation Animals Antioxidants Asthma Childhood Asthma Clinical Trials Data Dimerization Enzymes Epithelial Cells Extrinsic asthma FOXM1 gene Family Genetic Polymorphism Human Inflammation Lead Link Masks Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Matrix Obesity Oxidants Oxidation-Reduction Oxidative Stress PRDX3 peroxidase Pathogenesis Pathway interactions Patients Peroxides Placebos Population Production Public Health Randomized Reactive Oxygen Species Research Risk Factors Signal Pathway Signal Transduction Source Thinness Thiostrepton Universities Vermont airway epithelium allergic airway disease allergic airway inflammation allergic response asthmatic effective therapy member mitochondrial dysfunction mouse model novel therapeutics obesity treatment oxidation patient population placebo controlled trial transcription factor

项目摘要

Obesity is a risk factor for severe, uncontrolled asthma; the mechanisms causing asthma in obesity remain unclear, and so there is a lack of therapies for this patient population. Mitochondrial function is altered in both asthma and obesity, and oxidative stress is increased in obese compared with lean asthmatics. This project will address mitochondrial reactive oxygen species (mROS) signaling in obese allergic asthma. We have preliminary data that manipulating mROS signaling might inhibit allergic responses, particularly in obesity. We also have preliminary data implicating signaling of mROS through peroxiredoxin-3 (a mitochondrial peroxide target) and the transcription factor FoxM1 (a member of Forkhead box (Fox) family of transcription factors) in obese allergic asthma. This proposal will address the following hypothesis: mitochondrial redox perturbations induce oxidation of peroxiredoxin 3 which interacts with FoxM1 to enhance allergic airway inflammation and reactivity in obese allergic asthma; directly targeting mROS, and oxidant signaling through Prx3-FoxM1, will be effective for the treatment of obese allergic asthma. We will initially determine the functional significance of mROS production from airway epithelial cells from 4 patient groups (lean controls, obese controls, lean allergic asthmatics and obese allergic asthmatics), and the efficacy of inhibiting mROS production in mouse models of lean and obese allergic asthma using a mitochondrial targeted anti-oxidant, MitoQ. We will then determine the functional significance of Prx3 oxidation and interaction with FoxM1 in airway epithelial cells isolated from 4 patient groups (lean controls, obese controls, lean allergic asthmatics and obese allergic asthmatics), and the efficacy of inhibiting Prx3 and FoxM1 relay signaling in mouse models of lean and obese allergic asthma Finally we will perform a randomized, double-masked, placebo-controlled trial of the mitochondrial targeted anti-oxidant MitoQ in 40 patients with obesity and poorly controlled allergic asthma at two asthma research centers (University of Vermont, and Duke University). The results of these studies will show how mitochondrial ROS regulate allergic inflammation in obese asthma, and lead directly to novel therapies for the treatment of allergic asthma in obese patients.

肥胖是严重，不受控制的哮喘的危险因素。导致肥胖症哮喘的机制仍然存在不清楚，因此该患者人群缺乏疗法。线粒体功能都在两者中都改变了与瘦哮喘患者相比，肥胖的哮喘和肥胖症以及氧化应激增加。这个项目将涉及肥胖过敏性哮喘中的线粒体活性氧（MROS）信号。我们有初步的数据，即操纵MROS信号传导可能会抑制过敏反应，尤其是在肥胖。我们还拥有初步数据，暗示MRO通过过氧蛋白3（a）线粒体过氧化物靶标）和转录因子FOXM1（Forkhead Box（Fox）家族的成员转录因子）肥胖过敏性哮喘。该提案将解决以下假设：线粒体氧化还原扰动诱导氧化的氧化与FOXM1相互作用以增强肥胖的过敏性气道炎症和反应性的过氧化物毒素3 过敏性哮喘；直接靶向MRO，以及通过PRX3-FOXM1的氧化剂信号传导将有效肥胖过敏性哮喘的治疗。我们最初将确定来自4个气道上皮细胞MROS产生的功能显着性患者群体（精益控制，肥胖控制，瘦过敏性哮喘患者和肥胖过敏哮喘患者）和使用A抑制MROS产生的MROS产生的功效线粒体靶向抗氧化剂mitoq。然后，我们将确定PRX3氧化和与FoxM1相互作用的功能意义从4个患者组中分离出的上皮细胞（瘦肉对照，肥胖对照，瘦过敏性哮喘患者和肥胖过敏性哮喘患者），以及抑制PRX3和FOXM1继电器信号传导的功效肥胖过敏性哮喘最后，我们将进行线粒体靶向的随机，双掩蔽，安慰剂对照试验 40例肥胖症患者的抗氧化剂MITOQ在两项哮喘研究中中心（佛蒙特大学和杜克大学）。这些研究的结果将显示线粒体ROS如何调节肥胖哮喘的过敏性炎症，并直接导致肥胖患者治疗过敏性哮喘的新型疗法。