# Critical role of NRF2 in globin gene regulation in sickle cell disease mouse models

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $277,200

## Abstract

Project Summary/Abstract
Individuals with sickle cell disease (SCD) have severe anemia due to chronic red blood cell
hemolysis and increased oxidative stress producing endothelial cell dysfunction and
vasculopathy. Strategies to induce efficacious levels of γ-globin gene expression and fetal
hemoglobin (HbF) synthesis will alleviate SCD clinical symptoms. In addition, SCD phenotypic
severity is ameliorated by reducing oxidative stress. We previously demonstrated that
transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) is activated by dimethyl
fumarate as a mechanisms of HbF induction in erythroid progenitors. We also demonstrated an
essential role of NRF2 in ameliorating the severity of SCD using a novel NRF2 knockout SCD
mouse model established in our laboratory. To expand on these findings, we will determine the
molecular mechanism of NRF2-mediated γ-globin gene regulation and erythropoiesis through
DNA and histone epigenetic modifications during development. We will further assess the ability
of NRF2 activators in alleviating disease severity in SCD mouse models. Our Specific Aim is to
determine epigenetic mechanisms of NRF2-mediated globin gene regulation in the SCD mouse
model and develop novel HbF inducing agents. In Sub-aim A, we will determine the effects of
NRF2 knockout on erythroid differentiation and globin gene regulation. We will examine the
effects of NRF2 loss on erythropoiesis, metabolism and gene expression. The effects of NRF2
loss on HBB chromatin structure for DNA and histone epigenetic modifications in splenic
hematopoietic tissue will be investigated. In Sub aim B, We will evaluate the FDA-approved NRF2
activating drugs as novel HbF inducers. FDA-approved drugs, including dimethyl fumarate
(Tecfidera), Simvastatin (Zocor), and MLN9708 (Ixazomib), all NRF2 activators, will be tested.
The effect of NRF2 activators on erythropoiesis, HBB locus chromatin structure and in alleviating
disease severity in preclinical SCD mouse model will be determined. The knowledge gained will
reveal the critical role of NRF2 in globin gene regulation through epigenetic DNA and histone
modifications and validate the design of novel NRF2 activators for the treatment of SCD.

## Key facts

- **NIH application ID:** 10210388
- **Project number:** 5R01DK119762-03
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Xingguo Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $277,200
- **Award type:** 5
- **Project period:** 2019-09-17 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210388

## Citation

> US National Institutes of Health, RePORTER application 10210388, Critical role of NRF2 in globin gene regulation in sickle cell disease mouse models (5R01DK119762-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10210388. Licensed CC0.

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