# Genetic interactions and multifactorial genetics mediate myocardial regeneration

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $61,249

## Abstract

PROJECT SUMMARY/ABSTRACT
Dogma in the cardiovascular field argues that the adult mammalian heart is essentially non-regenerative and
that this failure to regenerate is primarily attributed to the post-mitotic and polyploid nature of most
cardiomyocytes (CMs). Multiple pieces of evidence now support the idea that within the adult mammalian
myocardium, mononuclear diploid cardiomyocytes (MNDCMs) are a privileged subpopulation of CMs that have
avoided this proliferative senescence. This attribute confers a unique capacity to re-enter the cell cycle and
regenerate myocardial tissue. Our recent work in mice demonstrates that the frequency of MNDCMs and the
competence to regenerate one's heart are two interlinked and variable traits influenced by the complex genetic
background of an individual. In other words, contrary to longstanding beliefs, some individuals can mount a
meaningful regenerative response after an insult, such as a myocardial infarction. We then took a genome-
wide association strategy to identify the genes associated with the observed variation. From this analysis, we
identified Tnni3k as one candidate that regulates CM senescence by inhibiting cytokinesis, specifically. Here,
we identify two new candidate genes each of which has a unique effect on CM cell cycle and ploidy.
Furthermore, we hypothesize that identified genes will work cooperatively to maximize the trait effect, thus a
multifactorial approach to heart regeneration is prudent. Aim 1 will explore the first novel candidate for its
independent effect on heart function and CM cell cycle activity in both uninjured and post-infarction settings. It
will also be tested in combination with Tnni3k. Aim 2 will examine the effect of the second novel candidate on
CM ploidy, cell cycle, and heart regeneration both independently and in combination with Tnni3k. Our prior
GWAS study affirms that CM ploidy and cardiac regeneration are complex phenotypes relying on multiple
genetic loci. Here, we use genetic approaches to modulate multiple candidate genes in a single animal model
and we anticipate that this combinatorial approach will potentiate CM proliferation and cardiac regeneration.

## Key facts

- **NIH application ID:** 11020490
- **Project number:** 3R01HL155085-04S1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Michaela Patterson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $61,249
- **Award type:** 3
- **Project period:** 2021-02-11 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11020490

## Citation

> US National Institutes of Health, RePORTER application 11020490, Genetic interactions and multifactorial genetics mediate myocardial regeneration (3R01HL155085-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11020490. Licensed CC0.

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