# Dissecting the cytoprotective role of NRF1 in heart regeneration and repair

> **NIH NIH K99** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $94,880

## Abstract

Project Summary
Heart failure is the leading cause of death in the world. At the core of the pathophysiology of heart failure is the
inability of the adult mammalian heart to regenerate following injury. In contrast to adults, the newborn mouse
heart is capable of complete regeneration following various types of injury, providing a new inroad into possible
mechanisms of cardiac regeneration and repair. Previously, we discovered that Nuclear Factor Erythroid-derived
2-related factor 1 (NFE2L1, also known as NRF1) is highly expressed in a regenerative cardiomyocyte population
in neonatal mouse hearts. Although NRF1 does not directly promote cardiomyocyte proliferation, it confers strong
protection to cardiomyocytes under stress conditions both in vitro and in vivo. Recent studies show that NRF1
regulates proteostasis and redox balance in multiple tissues in response to cellular stress, while its cardiac
functions are largely unknown. This proposal outlines a comprehensive plan to further dissect the biological and
pathological functions of NRF1 in cardiomyocytes to provide critical insight into the protective mechanism that
underlies regeneration and stress adaptation in the heart.
In this research plan, Aim 1 will establish how NRF1 protects neonatal cardiomyocytes. Aim 2 will demonstrate
the function of NRF1 in mammalian neonatal heart regeneration. Aim 3 will uncover the role of NRF1 as a stress
regulator in adult hearts following ischemic injury. In the mentored phase, Aims 1 and 2 will be carried out in the
laboratory of the renowned molecular biologist Dr. Eric Olson, and will generate data and mouse knockout
models for continued investigation in the independent phase. Aim 3 will be initiated during the K99 phase and
continued during the independent phase, dedicated to investigating the therapeutic potential of NRF1 to treat
adult ischemic heart disease. In order to gain research independence through mentored training, I will continue
to develop expertise in applying transcriptome profiling, including single-nucleus RNA sequencing, to study
neonatal heart regeneration (Aims 1 and 2). Such an experience will complement my prior training and constitute
an important data generating platform throughout my career. The proposed research requires that I acquire
additional mentoring in adult cardiac injury models and related cardiovascular phenotyping (Aim 3). Investigation
of NRF1 and its downstream pathways in regulating the stress response of cardiomyocytes during this mentored
training will lead to the establishment of an independent niche for my own academic career. In summary, this
application will provide me with the scientific training, mentoring, and career development necessary as I
transition to independence. Most importantly, the collective body of work generated through the completion of
the proposed aims will make major contributions to the field of cardiovascular science.

## Key facts

- **NIH application ID:** 10397102
- **Project number:** 5K99HL153683-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Miao Cui
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $94,880
- **Award type:** 5
- **Project period:** 2021-05-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397102

## Citation

> US National Institutes of Health, RePORTER application 10397102, Dissecting the cytoprotective role of NRF1 in heart regeneration and repair (5K99HL153683-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10397102. Licensed CC0.

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