# Models of Fuchs Corneal Endothelial Dystrophy

> **NIH NIH R21** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $237,750

## Abstract

Mouse models of Fuchs corneal endothelial dystrophy
Fuchs endothelial corneal dystrophy (FECD) affects 4% of people over age 40 in the USA and is more prevalent
in woman than men. Corneal endothelial (CE) cells control the hydration of the cornea necessary for its
transparency. In FECD there is thickening of Descemet’s membrane (DM) with formation of DM deposits called
guttae and CE cell death leading to corneal edema. Regardless of the specific mutation associated with FECD
a common characteristic is mitochondrial dysfunction leading to oxidative stress and apoptosis. The Col8a2
knock in (KI) mouse presents guttae but not mitochondrial reactive oxygen species (ROS) or corneal edema. A
second model of acute UV irradiation induces ROS, cell death and guttae but does not recapitulate the slow
FECD clinical course. Hence, the available models are not a complete representation of FECD. We have
previously observed that SOD2 knock down in CE cells in vitro leads to increased ROS production and apoptosis.
Our hypothesis is that addition of mitochondrial ROS in the Col8a2 model will provide a better representation of
human FECD.
In aim 1A&B Sod2 flox mice are crossed with mice expressing Estrogen receptor-Cre recombinase fusion protein
(CreERT). Upon Tamoxifen induction Sod2 KO is produced. We expect to see oxidative stress, guttae and
corneal edema before 1 year of age. In aim 1C we will induce Sod2 KO in Col8a2 KI mice. We anticipate an
acceleration of the appearance of guttae and the decrease in CE density leading to edema before 1 year of age.
In aim 2 we will generate a CE-predominant inducible KO system. In aim 2A we will generate a KI mouse (Col8a2-
IRES-rtTA) that contains an internal ribosome entry site followed by a reverse tetracycline transcription activator
coding sequence right after the stop codon of Col8a2 gene. It will be expected that Col8a2 and rtTA will be
translated from the same mRNA. These mice will be crossed with mice expressing Cre recombinase under the
tetracycline response element (TetO-CRE) and with Tomato-Green reporter mice (mT/mG). Hence, in Col8a2-
IRES-rtTA//TetO-CRE//mT/mG mice after Doxycycline (Dox) treatment, green fluorescence is expected only in
the CE and not in corneal epithelium and keratocytes. In aim 2B we will create a CE-specific inducible Sod2 KO
by Dox induction in mice of the genotype Col8a2-IRES-rtTA// TetO-CRE// Sod2 flox/flox. In this model we expect
a phenotype like the one described for specific aim1A&B. Establishing a good FECD model in mice will facilitate
the study of the pathological events and enable testing medical therapies. The generation of a CE-specific
inducible KO system will further facilitate the study of pathways of disease and the creation of new corneal
endothelial dystrophy models.

## Key facts

- **NIH application ID:** 10868104
- **Project number:** 1R21EY036160-01
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Diego Ogando
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $237,750
- **Award type:** 1
- **Project period:** 2024-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868104

## Citation

> US National Institutes of Health, RePORTER application 10868104, Models of Fuchs Corneal Endothelial Dystrophy (1R21EY036160-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10868104. Licensed CC0.

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