# Molecular Mechanisms of Severe Diabetic Retinopathy

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $426,561

## Abstract

Abstract:
Major causes of vision loss in people with diabetes include diabetic macular edema and severe diabetic
retinopathy (including severe non-proliferative diabetic retinopathy and proliferative diabetic retinopathy), both of
which are associated with extensive injury of retinal endothelial cells; however, the molecular mechanisms
underlying the progressive damage to endothelial cells in diabetes are poorly understood. Further, despite
preventable measures, severe diabetic retinopathy still occurs in a large number of diabetic individuals eventually
leading to blindness. Thus, identifying novel molecular targets to prevent the progression of diabetic retinopathy
is an unmet need. In this project, we propose to test the role of NADPH oxidase 4 (Nox4) in retinal endothelial
cells as a novel molecular target for the prevention and treatment of severe diabetic retinopathy. In recent studies,
we have shown that Nox4 is a major isoform of NADPH oxidases in retinal endothelial cells and Nox4 expression
is upregulated in retinal blood vessels in animal models of diabetic retinopathy. Genetic ablation of Nox4 gene
in endothelial cells reduces retinal vascular permeability in diabetic mice and alleviates aberrant new vessel
growth in oxygen-induced retinopathy. In contrast, overexpression of Nox4 in endothelial cells is sufficient to
induce retinal vascular leakage and degeneration. Furthermore, a recent genome-wide association study (GWAS)
identified Nox4 as a potential risk gene for severe diabetic retinopathy. Collectively, these experimental and
clinical findings suggest an important role of Nox4 in diabetes-mediated endothelial cell injury and retinal
vasculopathy. However, the mechanisms by which Nox4 induces endothelial injury and its relevance to human
disease remain an understudied area. In this project, we will first characterize Nox4 expression in human retinas
with different stages of diabetic retinopathy. Using an inducible endothelial cell specific conditional knockout
mouse line, we will delete Nox4 at various time points after diabetes onset to establish the role of endothelial
Nox4 in the development and progression of diabetic retinopathy. We will investigate the mechanisms of Nox4-
mediated endothelial death and senescence and elucidate novel signaling pathways activated by Nox4
upregulation in endothelial cells. Finally, we will test novel pharmacological inhibitor that specifically targets Nox4
for its preventive and therapeutic effects on diabetic retinopathy. We anticipate that the successful completion of
the proposed studies will not only provide mechanistic insight of diabetic retinopathy but also develop new
treatment that targets a risk gene identified by human genetic study for prevention of severe diabetic retinopathy.

## Key facts

- **NIH application ID:** 9865555
- **Project number:** 1R01EY030970-01
- **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:** 2020
- **Award amount:** $426,561
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865555

## Citation

> US National Institutes of Health, RePORTER application 9865555, Molecular Mechanisms of Severe Diabetic Retinopathy (1R01EY030970-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9865555. Licensed CC0.

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