# Molecular clock dysfunction in lung cellular senescence by environmental tobacco smoke

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $346,500

## Abstract

SUMMARY
Environmental tobacco smoke (ETS) or “secondhand smoke” exposure leads to stress-induced adverse
outcomes including cellular senescence and toxicological effects on the lungs associated with systemic
injury and inflammation in airway disorders. We have recently reported that ETS disrupts circadian clock
function, induces oxidative stress and stimulates abnormal inflammatory responses. REV-ERBα is a critical
component of the molecular clock, which regulates the expression of core clock genes, pro-inflammatory and
pro-senescent mediators. Our preliminary data suggest that ETS-mediated cellular senescence is
dependent on irregular activity of the clock gene nuclear receptor REV-ERB in the lungs. Our preliminary
data further show an impaired DNA repair and inflammatory response in molecular clock deficient REV-ERBα
KO mice, suggesting the involvement of the clock protein REV-ERB in regulating DNA damage/repair.
Further, REV-ERBα agonists reduce ETS-induced levels of pro-inflammatory and pro-senescent mediators.
However, the role of molecular clock dysfunction in chronic ETS-mediated DNA damage/repair, cellular
senescence, and toxicological effects remains unknown. Sirtuin 1 (SIRT1), a protein/histone deacetylase, is
reduced by ETS, resulting in cellular senescence, oxidative stress and abnormal inflammatory responses. Our
preliminary data show that SIRT1 regulates REV-ERBα abundance. However, it is not known whether SIRT1
regulates lung cellular senescence and inflammatory responses through a REV-ERBα-dependent mechanism.
We hypothesize that ETS disrupts molecular clock function, specifically REV-ERBα abundance, resulting in
DNA damage-initiated cellular senescence through a SIRT1-dependent mechanism in pulmonary toxicity. We
propose to test this hypothesis by determining the impact of ETS-induced REV-ERBdisruption on cellular
senescence, DNA damage/repair, and toxicological responses in a mouse model based on the following three
Aims: Aim 1: Determine the molecular mechanism through which ETS-mediated disruption of REV-
ERBmolecular clock function leads to cellular senescence and senescence-associated inflammatory
phenotype (SASP); Aim 2: Determine the involvement of REV-ERB in DNA repair by non-homologous end
joining (NHEJ) during cellular senescence following ETS exposure; and Aim 3: Determine the role of SIRT1 in
regulating REV-ERB and DNA damage-induced lung cellular senescence following ETS.
The outcome of this proposal will unravel the role of the molecular clock in regulating DNA damage-induced
lung cellular senescence via a SIRT1-dependent mechanism during the xenobiotic response to ETS exposure.
In turn, our findings will have great translational potential for the development of pharmacological therapies
based on targeting molecular clock function to ameliorate lung cellular senescence and DNA damage following
chronic exposure to ETS.

## Key facts

- **NIH application ID:** 10330545
- **Project number:** 5R01ES029177-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** IRFAN RAHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $346,500
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330545

## Citation

> US National Institutes of Health, RePORTER application 10330545, Molecular clock dysfunction in lung cellular senescence by environmental tobacco smoke (5R01ES029177-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10330545. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*