# Nrf2 Protein Translation for Protection Against Tissue Injury

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $368,398

## Abstract

Project Summary/Abstract:
Myocardial infarction (MI) is an emergency state that requires immediate medical intervention. Coronary artery
bypass graft (CABG) surgery or angioplasty procedures have becoming standard but effective treatment.
Biomarkers of myocardial cell death are detected postoperatively in nearly all CABG patients or about 30% of
angioplasty patients. Cell death remains detectable in the myocardium even when patients appear to have
recovered from MI. The degree of cell death predicts the risk of developing heart failure and other
complications. Identifying cytoprotective genes and uncovering their mechanisms of action pave the way for
developing new therapies to reduce cardiac injury. Oxidative stress, as a result of ischemic or reperfusion
and/or major surgery, usually causes an inhibition of protein synthesis. We found that Nrf2 mRNA can escape
such general inhibition and be translated selectively. 5'UTR of Nrf2 mRNA was found to recruit La autoantigen
for ribosomal association and de novo Nrf2 protein translation. Nrf2 is best known as a transcription factor for
regulating the expression of antioxidant and detoxification genes. We have found that Nrf2 protects
mitochondria from oxidative injury by physical association. We propose to utilize high resolution LC-MS/MS
based proteomics, novel Nrf2 inducers in combination with transgenic animals, and in vitro and in vivo
experimental models to test the hypothesis that elevated Nrf2 protein plays an important role in preservation of
mitochondria and protection against myocardial injury. Aim 1 will investigate a novel pathway of Nrf2 induction
by de novo Nrf2 protein translation. Components in the La and ribosomal protein complexes will be uncovered
in an effort to understand the translational machinery under oxidative or ischemic stress in cardiomyocytes.
Aim 2 will reveal a novel mechanism of Nrf2 mediated cytoprotection by testing Nrf2 participation in
maintenance of mitochondrial integrity and metabolism. The domain of Nrf2 protein for physical interaction with
mitochondria or mitochondrial outer membrane proteins will be identified for testing the significance in
mitochondrial integrity, metabolism and mitophagy. Aim 3 will provide preclinical evidence for Nrf2 as the lead
for cardiac protection. The importance of de novo Nrf2 protein translation for cardiac protection will be
demonstrated using siRNA against La autoantigen. Contracting cardiomyocytes will be established for
selection of Nrf2 inducers with suitable therapeutic indices. Mitochondrial preservation and cardiac protective
effect of these compounds will be tested using Nrf2 overexpressing transgenics as a positive control. We have
accumulated a large volume of data to support the success of the project. Accomplishment of the proposed
work will not only provide needed answers to basic science questions, but also present the feasibility of a new
category of drugs for cardiac protection.

## Key facts

- **NIH application ID:** 10000108
- **Project number:** 5R01GM126165-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** QIN M CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,398
- **Award type:** 5
- **Project period:** 2018-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000108

## Citation

> US National Institutes of Health, RePORTER application 10000108, Nrf2 Protein Translation for Protection Against Tissue Injury (5R01GM126165-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000108. Licensed CC0.

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