# Calcineurin Regulates Cardiomyocyte Cell Cycle Through Meis1 and Hoxb13

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $405,000

## Abstract

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself
following injury. As a result, strategies to induce heart regeneration are of significant interest. Previously, our
group demonstrated that, unlike the adult heart, the early postnatal mammalian heart is capable of
regeneration following injury through proliferation of existing cardiomyocytes. We have shown that Meis1, a
TALE family homeodomain protein, promotes postnatal withdrawal from cell cycle by activating expression of
the cyclin dependent inhibitors p16 and p21. We, along with other investigators, have gone on to identify a
diversity of additional signaling mechanisms that act to either permit or restrict proliferation (increased
mechanical load, oxygenation, DNA damage response, etc.). This suggests that Meis1 does not work alone,
but must act as part of a network of regulatory processes, although, the molecular mechanisms linking these
processes are largely unknown. Moving forward, the goal of our current proposal is to integrate Meis1-
dependent mechanisms with the wider postnatal signaling network by identifying Meis1 cofactors and
regulators. Specifically, we will focus on defining the functional interaction of Meis1 with its cofactor Hoxb13 in
the postnatal heart and the role played by the Ca2+-activated protein phosphatase calcineurin (CN) in
regulating this interaction and its consequences. The postnatal increase in cardiac load is known to initiate a
signaling cascade that leads to cardiomyocyte hypertrophy and increased contractility. Activation of CN
provides fundamental signals that promote hypertrophic growth of cardiomyocytes. Our preliminary studies
suggest that CN also works in conjunction with a Meis1/Hoxb13 complex to suppress proliferative growth.
Thereby, postnatal activation of CN provides a signal that helps switch the mechanism of cardiac growth from
hyperplastic to hypertrophic. We hypothesize that CN promotes postnatal arrest of cardiomyocyte cell
cycle by mediating nuclear translocation of Meis1 and HoxB13. Our experiments are designed to (1)
examine the role of Hoxb13 as a Meis1 co-factor, (2) define the mechanism of CN regulation of Meis1 and
Hoxb13 function, and (3) test the ability of CN to control postnatal cell cycle and heart regeneration.
These studies will provide fundamental insights into the nature of the coordinating link between the postnatal
increase in cardiac load that drives hypertrophy, and suppression of the heart’s capacity for repair.

## Key facts

- **NIH application ID:** 9878124
- **Project number:** 5R01HL147276-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Hesham Sadek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878124

## Citation

> US National Institutes of Health, RePORTER application 9878124, Calcineurin Regulates Cardiomyocyte Cell Cycle Through Meis1 and Hoxb13 (5R01HL147276-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9878124. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*