Mitochondrial Redox Perturbations in Obese Allergic Asthma

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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.