# Molecular Clock REV-ERBα in COPD and its exacerbations

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $385,000

## Abstract

SUMMARY
Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of chronic morbidity and mortality
in the United States. As COPD progresses, patients develop more frequent and severe exacerbations induced
by viral and bacterial infections. We have recently reported that cigarette smoke (CS) causes abnormal
inflammatory responses in the lungs while also disrupting the circadian molecular clock in lung cells. Our
preliminary data suggest that CS-induced cellular senescence and the influenza virus-induced decline in
lung function are associated with molecular clock dysfunction in lung epithelial cells. REV-ERBα is a nuclear
receptor and critical component of the molecular clock that drives daily rhythms of metabolism and immune-
inflammatory responses. We have shown that airway and alveolar REV-ERBα levels are reduced in the lungs
of mice with emphysema and in the lungs of COPD patients, and during exacerbations. Further, REV-ERBα
agonists reduce CS-induced levels of pro-inflammatory and pro-senescent mediators. These data suggest that,
besides its function as part of the molecular clock, REV-ERBα also acts as a critical component of the immune-
inflammatory response to CS and may be a key player in the progression and exacerbation of COPD. Despite
these intriguing results, the role of REV-ERBα in CS-mediated DNA damage/repair and cellular senescence
and its involvement in influenza virus-mediated lung responses is not known. We hypothesize that the CS-
mediated reduction in REV-ERBα abundance potentiates lung cellular senescence and inflammatory
responses. Further, the loss of circadian protein leads to COPD development, progression, and produces more
severe influenza virus-induced exacerbations. We propose to test this hypothesis by determining the
mechanistic relationship between the CS-induced reduction of REV-ERBα levels, increased cellular
senescence, DNA damage/repair, emphysematous responses and virus-mediated decline in lung function and
mucus production in the following three Aims: Aim 1: Determine whether REV-ERBα protects against cellular
senescence and senescence-associated inflammatory responses during CS-induced COPD/emphysema;
Aim 2: Determine the mechanism whereby the interaction between REV-ERBα, RORα and HDAC3 regulates
CS-induced lung cellular senescence and inflammatory responses; and Aim 3: Determine whether REV-ERBα
protects against lung function decline and mucus hypersecretion in a mouse model of influenza virus-mediated
COPD exacerbation. This proposal will unravel the role of the nuclear receptor and clock protein REV-ERBα in
regulating lung cellular senescence and inflammatory responses during influenza virus-induced
COPD/emphysema exacerbations. In turn, this will have great translational potential for the development of
novel and potentially effective pharmacological therapies to ameliorate lung cellular senescence in COPD and
its exacerbations based on targeting REV-ERBα function in the lungs using a m...

## Key facts

- **NIH application ID:** 9891076
- **Project number:** 5R01HL133404-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** IRFAN RAHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891076

## Citation

> US National Institutes of Health, RePORTER application 9891076, Molecular Clock REV-ERBα in COPD and its exacerbations (5R01HL133404-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891076. Licensed CC0.

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