# Mechanistic evaluation of the role of circadian rhythms in acute lung injury and subsequent recovery

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $530,591

## Abstract

Project Summary
 Our overall aim is to define the mechanisms underlying the circadian regulation of acute lung injury
and subsequent recovery. Our published work shows that circadian rhythms confer a time of day specific
protection from Influenza A Virus (IAV) infection. Mice infected at dawn had 3-fold better survival than those
infected at dusk. While, we cannot clinically control the time of exposure to IAV, these data suggest that
altering the circadian health of the host could affect outcomes. In fact, disrupting circadian rhythms genetically
in mice, by deleting the core clock gene, Bmal1, worsened mortality from IAV. Further proof of the translational
relevance of our mechanistic work came from our analyses of the UK biobank which revealed that disrupted
circadian rhythms was an independent risk factor for Influenza related hospitalization. Severe influenza
infection is characterized by extensive immunopathology and dysplastic lung repair and regeneration, often
independent of viral burden. Both vaccines and anti-viral agents have limited efficacy. The current proposal
addresses this need in the field by exploring a novel target—circadian rhythms as determinant of outcomes in
IAV. Since the last submission, we have generated exciting preliminary data that shows that disruption of the
AT2 clock is associated with (a) worse acute mortality, immunopathology and necroptosis and (b)
delayed recovery in vivo and poor regeneration on organoid assays. Our overall goals are to:
 (1) Test the hypothesis that the disruption of the AT2 clock leads to a pro-inflammatory state at
baseline that is further exacerbated by IAV infection, thereby worsening necroptosis.
 (2) To test the hypothesis that the circadian clock contributes to lung regeneration through Wnt-
responsive regulation of the cell cycle via the Axin2+ epithelial niche.
 Our approach employs tissue specific circadian knock-out models induced in adulthood, circadian sampling
throughout 24hrs, other genetic/environmental models of circadian disruption and tools form lung regenerative
biology, customized to the circadian context. I have also gathered an outstanding team of collaborators and
consultants with expertise in cell death, circadian bioinformatics, lung regeneration and virology. Elucidating
these mechanisms is the critical next step towards modulating the host circadian rhythms for therapeutic
purposes. While, we use influenza as our model, the principles uncovered thus, should be generalizable to
other viral conditions of the lung.

## Key facts

- **NIH application ID:** 10299011
- **Project number:** 1R01HL155934-01A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Shaon Sengupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $530,591
- **Award type:** 1
- **Project period:** 2021-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299011

## Citation

> US National Institutes of Health, RePORTER application 10299011, Mechanistic evaluation of the role of circadian rhythms in acute lung injury and subsequent recovery (1R01HL155934-01A1). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10299011. Licensed CC0.

---

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