# Role of Oxidative Stress in Pathogenesis of Fuchs Endothelial Corneal Dystrophy

> **NIH NIH R01** · SCHEPENS EYE RESEARCH INSTITUTE · 2024 · $632,258

## Abstract

Project Summary/Abstract
Fuchs Endothelial Cornel Dystrophy (FECD), a common age-related dystrophy, which is more prevalent in
women and smokers, is of unknown etiology. In FECD, corneal endothelial (CE) cell loss is accompanied by
abnormal extracellular matrix (ECM) deposition in the form of guttae. Our laboratory was the first to link
oxidative DNA damage and mitochondrial dysfunction in FECD pathogenesis. Specifically, we have shown that
ultraviolet-A (UVA) light, by triggering estrogen oxidizing enzyme, CYP1B1, induced greatest FECD phenotype
in female and estrogen-treated male mice due to mitochondrial DNA (mtDNA) damage. Estrogen and UVA
induced ATM-driven G2/M cell cycle arrest; however, deficient DNA repair system, led to net DNA damage
resulting in senescent and endothelial mesenchymal transition (EMT) phenotypes seen in FECD. Still, a
unifying mechanism of how UVA and smoking induce greater FECD phenotype with guttae formation in aging
females is unknown. Building upon our previous findings, we propose to investigate if UVA, age, and smoking–
induced oxidant-antioxidant imbalance leads to polyploidy and fibrosis by causing cell cycle arrest-driven ECM
deposition; and if this imbalance causes activation of aryl hydrocarbon receptor (AhR), the upstream inducer of
CYP1B1, which leads to melatonin breakdown to N-acetylserotonin (increased NAS/melatonin ratio) and
estrogen oxidation affecting mitochondrial DNA repair and biogenesis resulting in senescence seen in FECD.
Our study is significant, as understanding the effect of environmental stressors on sex-dependent mechanisms
involved in CE cell loss will provide new treatment targets for FECD. To achieve these aims, we will use our
newly developed non-genetic mouse model of FECD along with immortalized human CE cell lines, aqueous
humor, and ex vivo specimens of genotyped FECD donors. Our Specific Aims are: Aim 1: Determine whether
UVA, age, and smoking lead to cell cycle-dependent polyploidization and subsequent senescence that results
in profibrotic phenotype in FECD. This aim is based on the hypothesis that G2/M phase arrest leads to
polyploidization of CE, which protects from acute injury, but with prolonged stress promotes senescence and
fibrosis seen in guttae formation. Aim 2: Determine whether AhR and CYP1B1 activation, from UVA and
smoking, increase NAS/melatonin ratio causing greater DNA damage and CE cell loss in females. This aim is
based on the hypothesis that co-stimulatory effect of estrogen on AhR activates the CYP-family of enzymes
that cause greater estrogen and melatonin metabolism in females in FECD. Aim 3: Determine the role of
mitochondrial melatonin metabolism on DNA repair and mitochondrial biogenesis during the cell cycle arrest.
This aim is based on the hypothesis that mitochondrial translocation of CYP1B1 increases NAS/melatonin ratio
and leads to cell cycle-dependent DNA repair deficiency and mitochondrial dysfunction in FECD and aging.

## Key facts

- **NIH application ID:** 10954664
- **Project number:** 2R01EY020581-15A1
- **Recipient organization:** SCHEPENS EYE RESEARCH INSTITUTE
- **Principal Investigator:** Ula V. Jurkunas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $632,258
- **Award type:** 2
- **Project period:** 2010-07-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10954664

## Citation

> US National Institutes of Health, RePORTER application 10954664, Role of Oxidative Stress in Pathogenesis of Fuchs Endothelial Corneal Dystrophy (2R01EY020581-15A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10954664. Licensed CC0.

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