# ER stress and diabetic retinopathy

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $437,394

## Abstract

Abstract:
Diabetic retinopathy is a common complication of diabetes characterized by progressive neurovascular injury
and the consequent retinal function deterioration. Currently there are no therapies that can effectively protect
retinal neurons, and thereby mitigate, or reverse, the visual dysfunction in diabetic patients. Developing such
therapies is an urgent and unmet need for the field. In the previous funding period, we identified that X-box
binding protein 1 (XBP1), a stress-inducible transcription factor, plays a central role in retinal cell adaptation to
chronic stressors in aging and diabetes. Conditional knockout (cKO) of XBP1 in the retina results in accelerated
retinal function decline, loss of retinal neurons, disruption of synapses, and aberrant microglia activation in the
retina with aging. Importantly, we found that XBP1 expression in the aging retina is gradually decreased and
activation of XBP1 in response to endoplasmic reticulum (ER) stress is reduced. We reasoned that the loss of
XBP1 impairs the ability of retinal cells to adapt to chronic stresses in aging, ultimately leading to neuronal
damage. We tested whether XBP1 is involved in neuronal adaptation to chronic stresses in diabetes. We found
that loss of XBP1 leads to early onset retinal function decline, neuronal loss, and enhanced Müller glia activation
in diabetic mice. Based on these findings, we hypothesize that XBP1-mediated stress response signaling is
crucial to maintaining functional and structural integrity of retinal neurons under naturally occurring or pathogenic
chronic stress conditions, thus, protecting against neurodegeneration in diabetes and aging. In current
application, we will delineate how XBP1 regulates retinal neuronal adaptation to metabolic stress in diabetes. In
particular, we will explore the mechanisms by which XBP1 protects retinal neurons through regulation of aerobic
glycolysis in photoreceptor cells. Taking advantage of the innovative technology of vis-OCT for retinal imaging,
we will identify the earliest change in retinal nerve fiber layer (RNFL) before any detectable retinal ganglion cell
loss in diabetic retinas. We will also measure the precise change of retinal metabolic rate of oxygen for a
comprehensive characterization of metabolic profiling of retinal neurons in diabetes. The in-depth information
generated from the proposed studies will fill the knowledge gap in understanding the role of aerobic glycolysis
and its regulation by XBP1 in retinal neuropathy in diabetes. In addition, our study to identify novel molecules
that regulate retinal neuronal metabolism will pave the way for new treatment to protect retinal neurons in diabetic
retinopathy.

## Key facts

- **NIH application ID:** 10107820
- **Project number:** 5R01EY019949-12
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Sarah X Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $437,394
- **Award type:** 5
- **Project period:** 2009-12-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107820

## Citation

> US National Institutes of Health, RePORTER application 10107820, ER stress and diabetic retinopathy (5R01EY019949-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107820. Licensed CC0.

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