# Sequence Variants Impacting Cardiomyocyte S-phase Activity in Inbred Mice Following Injury

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $494,270

## Abstract

Numerous studies have shown that induction of cardiomyocyte cell cycle activity can have a profound
beneficial impact on cardiac structure and function following myocardial infarction. It has also been shown that
genetic background can impact the intrinsic rate of cardiomyocyte cell cycle activity in mice. We have observed
that mice in a DBA/2J genetic background (abbreviated DBA) have very low levels of cardiomyocyte cell cycle
activity following myocardial infarction. However, when crossed with C57Bl6/NCR mice (abbreviated NCR), the
resulting (DBA x NCR)-F1 animals mice exhibit a marked increase in cardiomyocyte S-phase activity following
infarction, indicating the presence of an autosomal gene (or genes) in the NCR background which acts in a
dominant manner to facilitate cell cycle re-entry. Analysis of backcross mice established that this gene (or genes)
resides in a region of interest (ROI) located on the distal end of chromosome 3. The experiments proposed in
Aim 1 will test hypothesis that a single gene within the ROI is responsible for elevated cardiomyocyte S-phase
activity post-infarction. Candidate genes within this region will be identified based on expression patterns
observed in infarcted DBA vs. NCR hearts as well as by the presence of sequence variants predicted to impact
protein structure and/or activity. The candidates will be systematically tested by generating genetically modified
animals, subjecting them to myocardial infarction, and then monitoring the level of cardiomyocyte S-phase
activity; an induction of cardiomyocyte cell cycle activity would confirm that the candidate gene being tested is
responsible for the trait. The experiments proposed in Aim 2 will test the hypothesis that the elevated cell cycle
activity encoded by the NCR ROI alleles has a positive impact on the diminished cardiac function and adverse
myocardial remodeling which is encountered post-infarction. Congenic mice in a DBA genetic background which
retain heterozygosity on the distal end of chromosome 3 and thus carry the NCR allele (or alleles) which is a
major contributor to cardiomyocyte S-phase induction will be generated. The mice will then be subjected to
myocardial infarction and longitudinal functional analysis. Terminal analyses will include comprehensive
hemodynamic measurements as well as assessment of adverse remodeling (cardiomyocyte apoptosis,
hypertrophy and myocardial fibrosis); relative improvements in cardiac function and structure would indicate a
beneficial effect from the NCR-encoded cell cycle activity following myocardial injury. Ultimately, the identification
and validation of genes underlying intrinsic differences in cardiomyocyte cell cycle rates observed in different
strains of mice could suggest potential therapeutic targets with which to enhance regenerative growth in injured
hearts.

## Key facts

- **NIH application ID:** 10758952
- **Project number:** 5R01HL155218-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** LOREN J FIELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $494,270
- **Award type:** 5
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758952

## Citation

> US National Institutes of Health, RePORTER application 10758952, Sequence Variants Impacting Cardiomyocyte S-phase Activity in Inbred Mice Following Injury (5R01HL155218-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10758952. Licensed CC0.

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