# The complex genetics of heart regeneration

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $520,970

## Abstract

Project Summary
Shortly after birth, most mammalian cardiomyocytes (CMs) become postmitotic and
nonregenerative, concurrent with becoming polyploid (either binucleated or mononuclear
tetraploid). What controls this process has been unknown. As a result, though, it is generally
thought that the adult heart has too little regenerative capacity to appreciably recover after
injury. A subpopulation of mononuclear diploid CMs (MNDCMs), thought to be very small in
number, persists in the heart through adulthood and is a candidate cell type to support
endogenous heart regeneration. Using a wholly new conceptualization, we demonstrated in
inbred mice that the percentage of MNDCMs in the adult heart, and the degree of functional
recovery and of CM proliferation after adult heart injury, are both highly variable traits subject to
the combined influence of multiple polymorphic genes. We identified and confirmed the CM-
specific kinase Tnni3k as one such gene with polymorphic alleles that influence variability in the
adult level of MNDCMs and thereby in the level of CM regeneration after adult infarction.
Using this new understanding, the focus of this project is to elucidate the processes that cause
CMs to become polyploid and postmitotic, and the consequences of these processes. In Aim 1,
we will dissociate the two roles of Tnni3k in the natural neonatal heart after birth and in the adult
heart following injury; we propose that these are related but independent and both relevant to
the outcome after adult injury. In Aim 2, we propose to identify two new genes that also
influence how CMs remain proliferative or become postmitotic, and to confirm our insights
related to the regenerative capacity of MNDCMs. In Aim 3, we explore an unexpected influence
of Tnni3k in the proper function of the cardiac conduction system (the electrical system of the
heart), and how this role relates to the process of heart regeneration. In Aim 4, we invoke a
mechanistic understanding to unify these observations of CM regeneration and conduction.
The conceptual significance of this project is transformational: rather than heart injury resulting
inexorably in declining heart function as is currently believed, some individuals may have
substantial regenerative ability depending on their genetic and cellular composition.
Furthermore, these insights might be developed for therapeutics to improve heart regeneration
in all patients regardless of their genetic background. And finally, this project might explain why
the mammalian heart transitions in most individuals to become mostly postmitotic in the
postnatal period, even at the cost of loss of regenerative ability.

## Key facts

- **NIH application ID:** 9891094
- **Project number:** 5R01HL144938-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Henry M Sucov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $520,970
- **Award type:** 5
- **Project period:** 2019-03-14 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891094

## Citation

> US National Institutes of Health, RePORTER application 9891094, The complex genetics of heart regeneration (5R01HL144938-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9891094. Licensed CC0.

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