Document text
Principal Investigator: RAJU C REDDY
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
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 mice ± transgenic global or AEC-specific Nur77 deletion, in a standard CS-
induced murine COPD model. The results will elucidate a protective role in COPD of the receptor Nur77, and
may identify it as a promising new therapeutic target for specific agonists to treat a widespread fatal disease.
Terms: <9-cis-Retinoic Acid Receptor><Address><Adverse effects><Age><Agonist><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoptosis><Apoptosis Pathway><Apoptotic><Assay><Binding><Binding Sites><Bioassay><Biological Assay><COPD><Cause of Death><Cell Communication and Signaling><Cell Death Induction><Cell Nucleus><Cell Signaling><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Combining Site><Computer Simulation><Computer based Simulation><Covalent Interaction><Cytoplasm><DNA Binding><DNA Binding Interaction><DNA bound><Data><Disease><Disease Progression><Disorder><Down-Regulation><Dysfunction><Emphysema><Epithelial Cells><Esteroproteases><Exhibits><Functional disorder><Gene Transcription><Genes><Genetic Transcription><Human><In Vitro><Inflammation><Inflammatory><Inflammatory Response><Inhalation><Inhaling><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knock-out><Knockout><Ligand Binding><Ligands><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><Mediating><Methods><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Movement><Murine><Mus><NLS Peptide><New Agents><Nuclear><Nuclear Export><Nuclear Hormone Receptor Superfamily><Nuclear Hormone Receptors><Nuclear Localization Signal><Nuclear Localization Signal Peptide><Nuclear Orphan Receptor><Nucleus><Orphan><Oxidative Stress><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Peptidases><Peptide Hydrolases><Physiopathology><Pneumonitis><Prevalence><Programmed Cell Death><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Pulmonary Emphysema><Pulmonary Inflammation><RNA Expression><RXR><RXR Protein><Reactive Site><Receptor Activation><Receptor Protein><Research><Respiratory Epithelium><Response Elements><Retinoic Acid Receptor RXR><Retinoid X Receptors><Role><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smoker><Smoking><Structure of parenchyma of lung><Structure of respiratory epithelium><Testing><Therapeutic><Toxicology><Transcription><Transgenic Mice><Up-Regulation><Upregulation><ages><airflow limitation><airflow obstruction><airway epithelium><airway epithelium inflammation><airway inflammation><airway limitation><airway obstruction><airway remodeling><alveolar destruction><biological signal transduction><body movement><cease smoking><chronic obstructive pulmonary disorder><cigarette smoke><cigarette smoke exposure><cigarette smoke-induced><cigarette smoke-induced COPD><cigarette smoke-induced Chronic Obstructive Pulmonary Disease><cigarette smoke-induced inflammation><cigarette smoke-induced lung damage><cigarette smoke-induced lung injury><cigarette smoking><cigarette smoking-induced COPD><cigarette smoking-induced Chronic Obstructive Pulmonary Disease><cigarette use><computational simulation><computerized simulation><conformation><conformational><conformational state><conformationally><conformations><disease model><disease severity><disorder model><drug candidate><emphysematous><exposed human population><exposure to cigarette smoke><human exposure><improved><in silico><in vivo><innovate><innovation><innovative><insight><interventional strategy><knock-down><knockdown><lung function><lung injury><military veteran><mitochondrial><mouse model><murine model><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><obstructed airflow><obstructed airway><pathophysiology><pathway><pre-clinical><preclinical><promoter><promotor><pulmonary><pulmonary damage><pulmonary function><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><quit smoking><receptor><respiratory airway obstruction><respiratory inflammation><respiratory tract epithelium><respiratory tract inflammation><response><response to therapy><response to treatment><screening><screenings><smoking cessation><social role><stop smoking><therapeutic response><therapeutic target><therapy response><tool><toxicant><treatment effect><treatment response><treatment responsiveness><veteran population>