# Regulation of the Nrf2-mediated Antioxidant Defense In Diabetic Retinopathy

> **NIH NIH F31** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $32,209

## Abstract

Project Summary
Diabetic retinopathy is the leading cause of blindness in working age Americans, affecting more than a third
of the ~20 million individuals with diabetes. The pathogenesis of this disease is defined by a combination of
hyperglycemia and a reduction in insulin mediated signaling, which impacts retinal neurons, glia, and
vasculature. A unifying theory for the pathophysiology of diabetic complications suggests that the principle
pathways responsible for hyperglycemia-induced tissue damage are all linked to the accumulation of reactive
oxygen species (ROS). In diabetes, the retina exhibits an increase in the production of ROS and an impaired
capacity to reduce free radicals. My central hypothesis is that diabetes-induced expression of the stress
response protein regulated in development and DNA damage 1 (REDD1) inhibits the nuclear factor erythroid-
2-related factor 2 (Nrf2)-related antioxidant response in the retina, leading to increased oxidative stress and
retinal pathology. In support of my hypothesis, I present compelling preliminary data demonstrating that
diabetes-induced oxidative stress is attenuated in the retina of REDD1 knockout mice. In addition, expression
of Nrf2-responsive mRNAs is increased in the retina of REDD1 knockout mice and nuclear Nrf2 protein
expression and activity are enhanced in REDD1 knockout human MIO-M1 retinal cells in culture. I plan to
test my central hypothesis by pursuing the following specific aims: 1. Establish the impact of REDD1 on Nrf2
synthesis in experimental models of diabetes. 2. Delineate the impact of REDD1 on Nrf2 degradation in
experimental models of diabetes. To test my hypothesis, I will pursue an experimental protocol involving
model systems ranging from cell culture to intact mice, as well as cutting-edge technologies for analyzing
mRNA translation. This fellowship award will also provide two key training opportunities. First, I will train with
Dr. Sui Wang (Stanford University) to develop skills necessary to manipulate gene expression in the retina
in vivo. Subsequently, I will receive training from Dr. Alistair Barber (Penn State College of Medicine) to
develop the technical expertise to assess the impact of diabetes on retinal pathophysiology using optical
coherence tomography, electroretinograms, and virtual optomotry. With respect to outcomes, this project will
not only expand my skills and systems of analysis, but will also identify novel mechanisms that link the
molecular events caused by the diabetic metabolic environment to the development of retinal pathology.
Identification of such mechanisms is significant because it will validate new targets for the development of
preventive and/or therapeutic interventions aimed at addressing the molecular basis of diabetic retinopathy
and promoting healthy vision.

## Key facts

- **NIH application ID:** 9908331
- **Project number:** 1F31EY031199-01
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** William P Miller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,209
- **Award type:** 1
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908331

## Citation

> US National Institutes of Health, RePORTER application 9908331, Regulation of the Nrf2-mediated Antioxidant Defense In Diabetic Retinopathy (1F31EY031199-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9908331. Licensed CC0.

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