# Molecular Mechanisms Underlying Mammalian NADPH Oxidase Activation and Regulation

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $359,000

## Abstract

PROJECT SUMMARY
Maintenance of the reactive oxygen species (ROS) homeostasis is essential to preserve cell integrity and vital
for the survival and growth of almost all life. In multicellular organisms, ROS is actively generated outside of
the cell or near the cell membrane to protect against invading pathogens as well as in normal physiological
processes such as hormone biosynthesis. However, ROS are generally associated with causing damage to
proteins and DNA within cells. Excessive ROS production leads to oxidative stress and contributes to the
development of many chronic conditions such as aging, cancer, diabetes, cardiac disorders, and
neurodegenerative diseases. The NADPH oxidases, a family of membrane enzymes whose primary function is
to produce ROS, play an essential role in maintaining ROS homeostasis and thus serve as valid drug targets
for combatting numerous diseases associated with oxidative stress. NADPH oxidases generate ROS by
catalyzing cross-membrane electron transfer from cytosolic NADPH to extracellular oxygen. Mammals encode
seven NADPH oxidases: DUOX1-2 and NOX1-5. To date, little is known about the molecular mechanism
governing the activation and regulation of NADPH oxidase proteins, representing a critical knowledge gap. In
this proposal, an interdisciplinary research program will be established to study the working mechanism of
NADPH oxidases by combining cutting-edge structural biology techniques such as single-particle cryoEM with
biochemical, biophysical, and cell biology approaches. We aim to address the two fundamental questions
underlying the catalytic activity of NADPH oxidases: i) how do NADPH oxidases mediate cross-membrane
electron transfer to catalyze the production of ROS? And ii) how is the catalytic function of NADPH
oxidases activated and regulated at the molecular level? Using the DUOX1 as an example, we will
establish a molecular paradigm for understanding the structure-function relationship of NADPH oxidases. The
outcomes of our studies will advance our fundamental understanding of the NADPH oxidase biology and lay
the foundation for novel drug development strategies to combat oxidative stress.

## Key facts

- **NIH application ID:** 10376366
- **Project number:** 5R01GM141357-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Ji Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $359,000
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376366

## Citation

> US National Institutes of Health, RePORTER application 10376366, Molecular Mechanisms Underlying Mammalian NADPH Oxidase Activation and Regulation (5R01GM141357-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10376366. Licensed CC0.

---

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