# Cardiomyocyte cell cycle activity in injured hearts

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $393,750

## Abstract

Cardiomyocyte cell cycle induction offers the potential for restoration of myocardial mass, and consequently
contractile function, following cardiac injury. Considerable effort has thus been invested studying the degree to
which cardiomyocytes can reenter the cell cycle and progress through cytokinesis in normal and injured adult
mammalian hearts. Using a transgenic reporter system to identify cardiomyocyte nuclei in tissue sections in
conjunction with continuous BrdU infusion, we have developed a digital imaging and analysis system which
permits both quantitation and 3D anatomical mapping of cumulative cardiomyocyte S-phase activity across the
entire heart. Using this system, we observed discrete clusters of cardiomyocyte S-phase activity in mice with
permanent coronary artery ligation. We also observed very high rates of cardiomyocyte S-phase activity in the
remote myocardium of mice with ischemia/reperfusion (I/R) injury. The studies proposed in this application will
identify the underlying mechanistic basis for the differential cardiomyocyte cell cycle responses observed
following myocardial injury. In Specific Aim 1, the variability in cardiomyocyte S-phase induction and cell cycle
progression following permanent coronary artery ligation will be established and the resulting data sets will
then be used for mathematical modeling with the goal of establish sampling criteria to quantitate total heart
cardiomyocyte S-phase activity which takes into account these intrinsic anatomical variations. Other studies
will determine if the observed clusters of S-phase activity arise from the clonal expansion of a subset of
cardiomyocytes which retain the potential for cell cycle reentry. In Specific Aim 2, I/R injury will be performed
in reporter mice maintained in an inbred genetic background to determine if the nature and/or degree of injury
are responsible for high levels of cell cycle induction in the remote myocardium. Other studies will utilize
informative backcrosses to determine the extent to which modifying genes can impact cardiomyocyte cell cycle
reentry following I/R injury. In both Aims, the degree to which the S-phase positive cardiomyocytes progress
through the cell cycle will also be quantitated. The proposed experiments will establish a 3D atlas of
cardiomyocyte S-phase activity in response to commonly used and clinically relevant injury models, and will
establish the degree to which increased levels of cardiomyocyte DNA synthesis contribute to polyploidization,
multi-nucleation, and/or cardiomyocyte renewal. In addition, these experiments will characterize the impact of
gender, genetic background and mode of injury on the magnitude of cardiomyocyte cell cycle reentry, as well
as determine the consequences of natural variation in cardiomyocyte cell cycle activity on cardiac function
post-injury. These data will provide useful insight for the development of interventional strategies with which to
promote regenerative growth of the heart, a...

## Key facts

- **NIH application ID:** 9849789
- **Project number:** 5R01HL132927-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** LOREN J FIELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2017-02-06 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849789

## Citation

> US National Institutes of Health, RePORTER application 9849789, Cardiomyocyte cell cycle activity in injured hearts (5R01HL132927-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849789. Licensed CC0.

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