Circadian rhythms strongly influence cell cycle and proliferation, and play a fundamental role in the maintenance of gastrointestinal physiology. Various gastrointestinal functions show a daily rhythmicity including gastric acid secretion, motility and intestinal stem cell regeneration and function, thus suggesting that these rhythms are under circadian clock control. This recognition has led to the application of chronotherapy (i.e. finding the right target and timing for disease treatments) in the treatment of colorectal cancer, improving patient survival. Importantly, disruption of key components of the molecular oscillator that generates circadian rhythms, such as Per2 and Bmal1, promotes the development of gastrointestinal tumors, yet the molecular mechanisms that connect circadian rhythms and cell cycle, and the physiological significance of this coupling remain largely unknown. Intriguingly, circadian rhythms are dysregulated in most human cancers suggesting that cancer cells impair the circadian clock to achieve uncontrolled growth and proliferation. In the proposed project, we propose to: (1) elucidate the consequence of the coupling between the circadian clock and cell cycle by integrating computational simulations and experimental validations, and (2) determine whether circadian rhythms regulate cell proliferation and tumor development using mouse enteroids. Our results will lay a foundation for identifying potential targets and temporal regimens to treat cancer.

Public Health Relevance

Circadian rhythms are dysregulated in most human cancers suggesting that cancer cells impair the circadian clock to achieve uncontrolled growth and proliferation, but the roles of circadain rhythms in tumor development remains unknown. The proposed research will uncover fundamental roles of circadian rhythms in cell proliferation and tumor development. This will lay a foundation of identifying potential targets and temporal regimens to treat cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA227379-01
Application #
9517423
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Watson, Joanna M
Project Start
2018-07-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Organized Research Units
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Ballweg, Richard; Lee, Suengwon; Han, Xiaonan et al. (2018) Unraveling the Control of Cell Cycle Periods during Intestinal Stem Cell Differentiation. Biophys J 115:2250-2258