# Roles of circadian rhythms in gastrointestinal systems

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2021 · $361,419

## Abstract

PROJECT SUMMARY
Over 1 in 4 American workers are shift workers with frequent disruptions in their circadian rhythms and
increased risks of gastrointestinal (GI) diseases. Circadian rhythms influence fundamental GI
processes, including digestion, immunity, and regeneration of the GI epithelium. Thus, disruption of
circadian rhythms is associated with GI diseases ranging from peptic ulcers to cancer. Recent studies
demonstrated that the circadian clock influences the cell cycle and vice versa, but the nature and
consequences of this connection remain largely unknown. One major limitation is the lack of a tractable
model system to investigate the molecular basis of these interactions. To address this, we developed
3D mouse enteroids, or an in vitro “mini-gut”, as a system to identify the molecular mechanisms and
consequences of this coupling. This system allows manipulation and tracking of both cell cycle and
circadian clock components as gut stem cells undergo differentiation into specialized cells. Importantly,
we have demonstrated that mouse enteroids possess robust circadian rhythms, and mimic the
response of gene ablation that is observed in mouse intestine. Specifically, we demonstrated that the
circadian clock in Paneth cells regulate coordinated cell division cycles via intercellular WNT signaling
in enteroids, and elimination of circadian rhythms results in disrupted development of intestinal crypts.
In the proposed project, we will determine: (1) cell type-specific roles of circadian rhythms in the small
intestine, (2) WNT signaling-mediated intercellular coupling between the GI circadian clock and cell
cycle, (3) circadian clock-regulated epithelial barrier function, and (4) circadian clock and Paneth cell-
mediated innate immune response to Salmonella infection. Our results will lay a foundation for
identifying potential targets and temporal regimens to restore circadian clock-dependent adult stem cell
regeneration, epithelial barrier function, and innate immune response for GI-related diseases.

## Key facts

- **NIH application ID:** 10163172
- **Project number:** 5R01DK117005-04
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** CHRISTIAN I HONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $361,419
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163172

## Citation

> US National Institutes of Health, RePORTER application 10163172, Roles of circadian rhythms in gastrointestinal systems (5R01DK117005-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10163172. Licensed CC0.

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