# Nur77: Novel Mechanistic Insights and Activation in COPD

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10726598
- **Project number:** 5I01BX004844-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** RAJU C REDDY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726598

## Citation

> US National Institutes of Health, RePORTER application 10726598, Nur77: Novel Mechanistic Insights and Activation in COPD (5I01BX004844-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10726598. Licensed CC0.

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