# The circadian clock as an age sensor in asthma resolution

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $777,497

## Abstract

ABSTRACT
We propose to study how the innate response to virus changes as children mature, which we theorize
contributes to asthma remission. Although asthma is a chronic disease, its symptoms vary greatly based on
the season, time of day, and age. Asthma seasonality is driven by respiratory virus outbreaks2, 3. Time-of-day
variations arise from the circadian clock, which regulates lung remodeling after respiratory viral infection4-6. The
least understood is why age affects asthma activity, and particularly why asthma exacerbations gradually
resolve in 50% of children as they mature7, 8. Understanding the biological processes that cause asthma
resolution in children could yield ways of promoting remission in all patients. We hypothesize that asthmatic
children experience fewer asthma exacerbations as they age because they develop a pro-resolution response
to viruses, preventing new type-2 inflammation and airway remodeling from forming with each new infection.
We further hypothesize that circadian clocks operating within alveolar macrophages (AMs) and airway
epithelial cells are critical for this pro-resolution response. Our hypotheses arise from observations that, in
children, viruses become less potent at triggering asthma exacerbations as children mature. In mice,
respiratory viral infections that produce chronic lung remodeling in juvenile animals fail to do so in adults. The
protection afforded by adult age correlates with a blunted type 2 inflammatory response to viruses. AMs are
required for adult protection from post-viral lung disease and exhibit a distinct transcriptional and
immunophenotypic profile. Protection is also marked by reduced accumulation of dysplastic Krt17+ basal cells
after respiratory viral infection. Finally, these age-related benefits are negated by circadian clock disruption,
leading otherwise protected adult mice to develop chronic post-viral lung disease like juveniles. This project will
clarify how the circadian clock mediates the adult age, pro-resolution response to viral asthma triggers.
Proposed experiments in mice use Sendai virus (SeV) as a viral model of asthmatic lung remodeling and
Alternaria alternata extract as an allergic model that serves as a comparator. We will employ complementary
genetic and environmental methods to disrupt circadian clock function (clock gene Bmal1 deletion and chronic
jet lag or CJL). Aim 1 focuses on how the adult-age AM clock promotes the resolution of viral inflammation.
Aim 2 focuses on how the adult-age epithelial clock promotes the normal repair of viral airway injury. We will
analyze antiviral function in airway cells from asthma remission patients for the first time. This project aligns
with NIH research priorities and satisfies the recent Notice of Special Interest NOT-HL-22-043: Basic and
Translational Research on Circadian Regulation of Heart, Lung, Blood, and Sleep Disorders.

## Key facts

- **NIH application ID:** 10979249
- **Project number:** 1R01HL172823-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jeffrey Adam Haspel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $777,497
- **Award type:** 1
- **Project period:** 2024-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979249

## Citation

> US National Institutes of Health, RePORTER application 10979249, The circadian clock as an age sensor in asthma resolution (1R01HL172823-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10979249. Licensed CC0.

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