# Sex dependent regulation of retinal degeneration

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $240,019

## Abstract

Summary:
Retinal detachment (RD), which is caused by injury or retinal disorders such as age-related macular
degeneration and diabetic retinopathy, is a leading cause of retinal degeneration and vision loss. In patients with
sustained RD, progressive visual decline due to photoreceptor cell death is common, and leads to a significant
decrease in visual acuity. However, the underlying biological processes controlling photoreceptor cell death in
this context are not well understood, and currently no treatments exist aside from surgery to reattach the retina.
Cell death during RD is caused by the physical separation between photoreceptors and the choroid and RPE,
their primary sources of oxygen and nutrients, resulting in acute ischemia and metabolic distress. Our preliminary
data has demonstrated that male mice with a RD have a significant increase in photoreceptor cell death
compared to their female counterparts. Moreover, we have identified estrogen as a key modulator of
photoreceptor susceptibility to RD injury. In many neurodegenerative diseases of the brain, estrogen confers
neuroprotection by improving mitochondrial function and reducing oxidative damage.
The goal for this work is to test the hypothesis that females are protected from RD-induced retinal degeneration
through the actions of estrogen-dependent normalization and/or rescue of photoreceptor metabolic dysfunction.
We will utilize a well-defined mouse model of RD, in which a subretinal injection of sodium hyaluronate is used
to create a detachment. The mouse RD model will allow us to take advantage of well-established genetic
manipulation platforms in mice in a controlled setting. In order to characterize the role of sex and the estrogen
signaling system in photoreceptor cell death we will: 1) Define how estrogen signaling is modulated in vivo using
genetic models and gonadectomy to precisely delineate the signaling pathways and metabolic processes
involved in estrogen-dependent rescue of photoreceptor degeneration; 2) Elucidate the role of estrogen in
alleviating mitochondrial stress and oxidative damage in photoreceptors in response to RD; 3) Delineate the
specific metabolic pathways, key metabolites and mitochondrial functions involved in the sex dependent
regulation of cell death in RD by SeaHorse analysis. It is our belief that this study will yield insights into the role
of estrogen in retinal neuroprotection and provide new sex specific therapeutic targets and/or treatment
modalities for the management of sight-threatening diseases such as RD.

## Key facts

- **NIH application ID:** 10133429
- **Project number:** 3R01EY029269-02S1
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Kip M Connor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $240,019
- **Award type:** 3
- **Project period:** 2019-04-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133429

## Citation

> US National Institutes of Health, RePORTER application 10133429, Sex dependent regulation of retinal degeneration (3R01EY029269-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133429. Licensed CC0.

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