Mitochondrial Redox Perturbations in Obese Allergic Asthma

肥胖是严重的、不受控制的哮喘的危险因素;肥胖引起哮喘的机制仍然存在 目前尚不清楚，因此缺乏针对该患者人群的治疗方法。线粒体功能在两种情况下都发生了改变， 哮喘和肥胖，与瘦型哮喘患者相比，肥胖患者的氧化应激增加。该项目将 研究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 肥胖我们也有初步的数据表明mROS通过过氧化物氧还蛋白-3（a 线粒体过氧化物靶点）和转录因子FoxM 1（Forkhead box（Fox）家族的成员） 转录因子）在肥胖过敏性哮喘中的作用。 该提案将解决以下假设：线粒体氧化还原扰动诱导 与FoxM 1相互作用的过氧化物氧还蛋白3增强肥胖者的过敏性气道炎症和反应性 过敏性哮喘;直接靶向mROS和通过Prx 3-FoxM 1的氧化剂信号传导，将对哮喘有效。 治疗肥胖过敏性哮喘。 我们将初步确定从4个气道上皮细胞产生mROS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）， 在瘦型和肥胖型过敏性哮喘小鼠模型中， 线粒体靶向抗氧化剂MitoQ。 然后，我们将确定气道中Prx 3氧化和与FoxM 1相互作用的功能意义。 从4个患者组（瘦对照组、肥胖对照组、瘦过敏性哮喘患者和肥胖患者）分离的上皮细胞 过敏性哮喘），以及抑制Prx 3和FoxM 1中继信号传导在瘦和 肥胖过敏性哮喘 最后，我们将进行一项随机、双盲、安慰剂对照试验， 两项哮喘研究中40例肥胖和控制不良的过敏性哮喘患者的抗氧化剂MitoQ 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如何调节肥胖性哮喘的过敏性炎症， 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.