# Epigenetic Regulation of Gene Expression in the Aging Eye

> **NIH NIH R01** · PURDUE UNIVERSITY · 2020 · $376,148

## Abstract

Oxidative stress contributes to the development and progression of age-related ocular diseases such as age-
related macular degeneration, cataracts, glaucoma and diabetic retinopathy. The eye is particularly vulnerable
to oxidative stress due to its high metabolism, oxygen content and light exposure. Cells respond to reactive
oxygen species by inducing expression of genes that counteract these toxic compounds, but aging impairs the
ability of cells to activate these cytoprotective gene expression programs. Induction of stress response genes
requires epigenetic mechanisms, and our preliminary studies show that these epigenetic mechanisms are
essential in photoreceptors to prevent premature retinal degeneration. Notably, many of the epigenetic factors
that protect photoreceptors are themselves subject to protein oxidation, and oxidative stress directly inhibits
activity of two of these proteins in vitro. Here, we hypothesize that oxidative stress inhibits the epigenetic
mechanisms required for stress gene induction in aging photoreceptors, leading to increased risk of retinal
degeneration. In this model, increased oxidative stress due to smoking or other environmental factors, could tip
the balance towards ocular disease by impairing the epigenetic mechanisms that are necessary for
neuroprotective gene expression. To test this model, we will identify the genes induced by oxidative stress in
photoreceptors during aging and in response to blue light, which induces oxidative stress, in the genetically
tractable model system Drosophila. Next, we will test if prolonged oxidative stress impairs induction of stress
response genes by profiling nascent transcription in photoreceptors exposed to blue light. We have identified 22
epigenetic factors that are required for survival of old photoreceptors, and we will test if these factors increase
susceptibility to oxidative stress and are necessary for stress gene induction in photoreceptors. Last, we will
characterize the redox proteome of eyes exposed to oxidative stress and test if oxidative stress inhibits the
activity of histone modifying enzymes in vitro. Together, these studies will identify the epigenetic factors that are
susceptible to inactivation by oxidative stress, but that are also necessary for photoreceptors to cope with
oxidative stress. In the long-term, these epigenetic mechanisms could be targeted therapeutically by generating
oxidative-insensitive proteins that could enhance the resistance of old photoreceptors to oxidative stress.

## Key facts

- **NIH application ID:** 9962541
- **Project number:** 2R01EY024905-06
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Vikki Marie Weake
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,148
- **Award type:** 2
- **Project period:** 2015-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962541

## Citation

> US National Institutes of Health, RePORTER application 9962541, Epigenetic Regulation of Gene Expression in the Aging Eye (2R01EY024905-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9962541. Licensed CC0.

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