Mitochondrial Redox Perturbations in Obese Allergic Asthma

肥胖是严重的、无法控制的哮喘的危险因素；导致肥胖的哮喘的机制仍然存在。 不清楚，因此缺乏针对这一患者群体的治疗。两者的线粒体功能都发生了改变。 与瘦型哮喘患者相比，肥胖者的哮喘和肥胖以及氧化应激增加。这个项目将 解决肥胖过敏性哮喘的线粒体活性氧簇(MRO)信号转导。 我们有初步数据表明，操纵MROS信号可能会抑制过敏反应，特别是在 肥胖。我们也有初步数据表明MRO通过过氧化还蛋白-3(A)传递信号。 线粒体过氧化物靶基因)和转录因子FOXM1(Forkhead box(Fox)家族成员 转录因子)在肥胖过敏性哮喘中的作用。 这项建议将解决以下假设：线粒体氧化还原扰动导致氧化 过氧化还蛋白3与FOXM1相互作用增强肥胖症患者过敏性呼吸道炎症和反应性 过敏性哮喘；直接靶向MRO，以及通过Prx3-FOXM1传递氧化剂信号，将对 肥胖性过敏性哮喘的治疗。 我们将初步确定呼吸道上皮细胞产生MRO的功能意义。 患者组(瘦对照组、肥胖对照组、瘦过敏性哮喘患者和肥胖过敏性哮喘患者)，以及 阿司匹林抑制瘦型和肥胖型过敏性哮喘小鼠模型MROS产生的效果 线粒体靶向抗氧化剂MitoQ。 然后我们将确定Prx3氧化的功能意义以及在呼吸道中与FOXM1的相互作用 从4组患者(瘦对照组、肥胖组、瘦过敏性哮喘患者和肥胖组)分离的上皮细胞 过敏性哮喘)，以及抑制Prx3和FOXM1继发信号的效果。 肥胖过敏性哮喘 最后，我们将进行一项随机、双盲、安慰剂对照的线粒体靶向试验 抗氧化剂MitoQ在40例肥胖和控制不良的过敏性哮喘患者中的两项研究 中心(佛蒙特州大学和杜克大学)。 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， 并直接导致治疗肥胖患者过敏性哮喘的新疗法。

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.