# The role of Pitx2 in heart injury and regeneration.

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $373,750

## Abstract

Project Summary
This proposal describes a five-year program to investigate the roles of paired-like homeodomain 2 (Pitx2)
signaling during cellular injury response and fibrotic scar formation after myocardial infarction (MI). MI accounts
for millions of deaths worldwide annually. Therefore, developing an effective regenerative therapy is one of the
major goals of modern cardiovascular biology. Pitx2, when overexpressed in cardiomyocytes, is capable of
partially repairing myocardium in a mouse MI model. Pitx2 function is induced and promoted by the upstream
nuclear factor erythroid 2 like 2 (Nrf2), a known regulator of redox balance. Unlike most of the regeneration-
promoting factors that induce cell cycle reentry in cardiomyocytes, the Pitx2 signaling only has a mild effect on
cardiomyocyte proliferation. Instead, Pitx2 regulates the expression of antioxidant scavengers and components
of respiratory chain, both are critical for cell survival and homeostasis. Our Preliminary studies also suggest a
role of Pitx2 in myofibroblast activity and fibrosis formation. Therefore, targeting Pitx2 for therapeutics provides
alternative strategies which focus on cell survival and removing fibrosis. However, an in-depth study of Pitx2 is
needed for designing an efficient targeting strategy. The Specific Aim 1 will test the hypothesis that
overexpression of Pitx2 promotes the degradation of Nrf2 by inducing the expression of E3 ubiquitin-protein
ligase Rbx1. This proposed negative feedback loop may promote the degradation of Nrf2, a key factor for the
nuclear translocation and activity of Pitx2. We aim to explain why Pitx2 overexpression in myocardium can only
partially repair the myocardium after MI. Transgenic mice with modified Pitx2 and/or Rbx1 expression will be
subjected to MI to examine the hypothesis. We will also test an improved therapeutic strategy by
overexpressing Pitx2 and Nrf2 simultaneously in infarcted cardiomyocytes. The Specific Aim 2 will focus on the
downstream effects of Pitx2 signaling and test the hypothesis that Pitx2 activity in cardiomyocytes inhibits the
transition of cardiac fibroblasts to myofibroblasts after MI. Preliminary data suggest that Pitx2 signaling in
cardiomyocyte can affect myofibroblast activity. We proposed an interaction between cardiomyocytes and
cardiac fibroblasts, coordinated by Pitx2, that can regulate fibrosis formation after MI. Mouse models with
modified Pitx2 expression and in vitro primary cell cultures will be used to examine how cardiomyocyte-derived
signaling can regulate fibroblast-to-myofibroblast transition, myofibroblast migration, and ECM deposition.

## Key facts

- **NIH application ID:** 10813087
- **Project number:** 5R01HL148728-05
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Ge Tao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $373,750
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813087

## Citation

> US National Institutes of Health, RePORTER application 10813087, The role of Pitx2 in heart injury and regeneration. (5R01HL148728-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10813087. Licensed CC0.

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