Endoplasmic Reticulum Stress Signaling in Allergen-induced Airway Remodeling

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 DESCRIPTION (provided by applicant): Incessant damage of epithelial layer and lack of ordered epithelial regeneration are known to be the hallmarks of lung remodeling. The endoplasmic reticulum (ER) stress plays a critical role in epithelial apoptosis, and the subsequent pathology of lung remodeling. Patients with asthma exhibit increased airway structural remodeling marked by collagen deposition and smooth muscle cell hypertrophy, which correlates with decreased lung function, morbidity, mortality and increased health care costs. However, the mechanisms regulating the key steps leading to airway fibrotic remodeling in asthma are unknown. Our novel preliminary results demonstrate that allergen house dust mite (HDM), causes severe ER stress, activation of ER stress transducer-transcription factor, ATF6, disulfide isomerase ERp57 and disulfide bridges in proapoptotic Bak, leading to apoptosis of airway epithelial cells and production of growth factors from the injured airway epithelium, which is associated with airway fibrotic remodeling in mice. Importantly, we also observed that deletion of ATF6a and ERp57 or treatment with a chemical chaperone; tauroursodeoxycholic acid (TUDCA) attenuated allergen induced airway fibrosis in mice. The central hypothesis to be addressed herein is that allergen exposure induces ER stress mediated apoptosis and injury to airway epithelial cells and subsequent production of fibrotic mediators leading to airway structural remodeling via the ATF6-ERp57-Bak signaling axis. In Specific Aim #1 we will determine the functional roles of ER stress transducer ATF6 in regulating allergen- induced expression of disulfide isomerase, ERp57, and subsequent induction of epithelial cell death and development of airway structural remodeling. The specific Aim #2 seeks to explore the functional requirement of allergen-induced protein disulfide isomerase ERp57 in disulfide mediated oligomerization of proapototic Bak to cause epithelial injury and subsequent development of airway remodeling. In Specific Aim #3 we will assess the efficacy of a chemical chaperone, TUDCA in alleviating ER stress and decreasing subsequent epithelial cell death, ultimately resulting in resolution of allergen-induced airway remodeling. We will use complementary human primary epithelial cell culture and mouse transgenic approaches, coupled with detailed biochemical analysis of these processes in mouse lung tissues. Completion of proposed experiments is likely to impart a significant knowledge on allergen-induced epithelial ER stress, and its transducers which may be targeted in the future using small molecule inhibitors to attenuate airway fibrosis. Furthermore, our project will evaluate the efficacy of a naturally occurring bile acid (TUDCA) in attenuating airway fibrosis. Given the dearth of treatment options in chronic asthma and fibrosis, TUDCA may prove to be an alternative therapeutic for treatment of airway remodeling.