Chronic obstructive pulmonary disease (COPD), usually caused by cigarette smoking, is rising in prevalence and is predicted to become the leading cause of death worldwide by mid-century. Available treatments provide only short-term benefit, and fail to stop COPD’s inexorable progression. Even smoking cessation, after the earliest stages, provides limited benefit. New mechanistic therapies to halt progression are thus urgently needed. COPD pathophysiology includes bronchial inflammation and remodeling, combined with septal destruction/emphysema driven by inflammation-associated oxidative stress and protease secretion. Inflammation-driven apoptosis of airway epithelial cells (AECs) is also thought to contribute to airway remodeling. Based on promising preliminary findings, the proposed research will test the novel hypothesis that agonist activation of the orphan nuclear hormone receptor Nur77 may have beneficial effects in COPD. Preliminary findings revealed that AECs and lungs of COPD patients and also lungs of mice with cigarette smoke (CS)-induced COPD exhibit marked downregulation of Nur77 expression. We also found that Nur77 knockout (KO) exacerbates CS-induced inflammation and lung damage in mice, suggesting a protective role of endogenous Nur77. We tested the effects of treatment with the classical Nur77 agonist cytosporone B and found it ameliorated CS-induced lung damage and inflammation in mice, leading us to hypothesize that Nur77 agonists may be useful in COPD therapy. Our in silico findings show that Nur77 exhibits dual (classical and alternate) ligand binding sites. No alternate site ligand had been identified, but to assess any potential beneficial effects of activating it we used in silico modeling to identify a novel compound that in vitro studies demonstrated binds to the Nur77 alternate site, and found that it is an agonist that activates Nur77 transcriptional activity more effectively than cytosporone B. CS extract in vitro causes AECs and type ll pulmonary ECs to become apoptotic, a pathway that potentially contributes to COPD. Nur77 localization to mitochondria is known to trigger apoptosis, leading us to hypothesize that CS extract is inducing movement of Nur77 from the nucleus to cytoplasm and thence to the mitochondria. Our preliminary data show that our novel alternate site Nur77 agonist reverses such COPD-associated cytoplasmic localization by anchoring Nur77 to its target response elements in the nucleus, thus ameliorating inflammation and apoptosis of lung ECs. Based on these novel findings, the aims are to: 1: Determine whether endogenous suppression of nuclear and total Nur77 activity that occurs in COPD promotes disease progression and severity. 2: Test if activating Nur77 ameliorates COPD severity and progression and its contributing lung EC apoptosis. We will achieve these aims by treating human AECs of healthy controls and COPD patients in vitro with our novel, effective Nur77 agonist, and testing its effects in m...