# Elucidating the Role of Multinuclearity in Healthy and Diseased Mammalian Cardiomyocytes

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $485,927

## Abstract

PROJECT SUMMARY
Heart Failure has resisted the downward trend in mortality seen in other diseases and new therapies are
needed. Heart failure is driven by the hypertrophy and loss of cardiomyocytes, which comprise the bulk of the
heart by volume and provide the main contractile force necessary to move blood throughout the body. Over
90% of cardiomyocytes in mammalian species are polyploidal and/or multinucleated. These extra copies of
DNA have been studied in the context of the low regenerative capacity of the heart, yet comparatively little
effort has focused on other potential adaptive or maladaptive effects of this increased nuclearity.
Historically, the large size of the mature cardiomyocyte has precluded its analysis using unbiased single cell
RNA sequencing. Research has focused on RNAseq in isolated nuclei, which by its very nature lacks
information about nuclearity within the studied hearts. Recently, new technology has allowed for unbiased,
high-throughput single cell RNAseq of whole, mature cardiomyocytes. When the results of these single cell
studies are compared to the isolated nuclei studies, researchers find that, using the same clustering
algorithms, there are approximately twice as many distinct cellular transcriptome clusters as there are distinct
nuclear transcriptome clusters. This result suggests the existence of a form of ‘nuclear code’ in which a
multinucleated cell’s transcriptome is ‘encoded’ by nuclei drawn from two or more nuclear clusters, a result
supported by observations from other multinucleated cell populations. These encoded cells could display
differences in contractility, resistance to apoptosis, or even proliferative potential, with significant implications
for cardiac function and the development of heart failure.
The goal of this Steven I. Katz proposal is to 1) Utilize cutting edge single cell and single nucleus sequencing
technology to identify and confirm this nuclear encoding, 2) Explore the spatial distribution of mono and multi-
nucleated cells across the heart, and 3) Identify how this encoding responds to genetic and environmental
perturbations in healthy and failing hearts. As requested by the mechanism, in this proposal we set forth a
plan for an ambitious new direction for our laboratory’s research, built upon rigorous work documented in the
literature and supported by collaborators and subject matter experts. The proposal combines bioinformatic,
imaging, and next generation sequencing approaches to identify how changes in the nuclear code of
multinucleated cardiomyocytes leads to differences in response to cardiac injury and stress. Upon completion,
this grant will result in a more complete understanding of the role of multinuclearity and polyploidy in the
mammalian heart, with subsequent revelation of numerous new avenues of research for diagnostic and
therapeutic approaches to combat heart failure.

## Key facts

- **NIH application ID:** 10793485
- **Project number:** 5R01HL162636-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Christoph Daniel Rau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,927
- **Award type:** 5
- **Project period:** 2023-03-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793485

## Citation

> US National Institutes of Health, RePORTER application 10793485, Elucidating the Role of Multinuclearity in Healthy and Diseased Mammalian Cardiomyocytes (5R01HL162636-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10793485. Licensed CC0.

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