# Corneal Endothelium – Extracellular Matrix Interactions

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $358,400

## Abstract

Fuchs endothelial corneal dystrophy (FECD) decreases vision quality and can progress to vision loss, for
which 17,000 individuals/year require corneal transplantation in the United States. The hallmarks of FECD are
the progressive accumulation of deposits (guttae) on the basement (Descemet’s) membrane of the corneal
endothelium and progressive loss of corneal endothelial cells (CEnCs). These changes are present in all forms
of FECD regardless of genetic background. But it is unknown how guttae form or how this contributes to CEnC
dysfunction. Novel preliminary data in support of this project show that guttae-like structures can be developed
in cell culture. Long-term culture of primary bovine CEnCs (BCEnCs) leads to guttae development in the
extracellular matrix (ECM) secreted by the cells. The guttae are most prominent under conditions of high
glucose and/or low oxygen, which are environments that favor glycolysis over oxidative respiration. The
pathological ECM developed under these conditions does not favorably support the growth of non-diseased
human CEnCs. The central hypothesis of this proposal is that a common pathway leading to the development
of guttae in the ECM of CEnCs is glycolytic metabolism from mitochondrial dysfunction. Furthermore, the
composition of the pathological ECM does not support the growth and metabolism needs of healthy CEnCs.
The objectives of the proposed studies are to identify the metabolic pathways that contribute to guttae
formation and to understand how pathological ECM disrupts CEnC function. The objectives will be achieved
with three Specific Aims. Aim 1 is to identify alterations in ECM composition resulting from oxygen stress in
CEnCs, and to compare those alterations to changes in FECD patient specimens. The composition of BCEnC-
secreted ECM, non-diseased human Descemet’s membrane, and patient FECD specimens will be compared
with quantitative proteomics analyses. Aim 2 is to discover CEnC stressors that lead to the formation of guttae.
BCEnCs will be subjected to disruptors of mitochondrial respiration and glycolysis to determine the conditions
favoring guttae formation. Aim 3 is to analyze the growth and metabolic profile of human CEnCs grown on
pathological ECM and the role of the actin cytoskeleton. Human CEnCs will be seeded on pathological ECM
for measurements of cell growth, cell stiffness (a measure of the actin cytoskeleton), mitochondrial
morphology, and cellular respiration. Successful completion of the proposed studies will provide (i) a biological
model with guttae generation for studying CEnC–ECM interactions where both components can be
manipulated, (ii) insight into how metabolic stressors of CEnCs that are potential targets for future therapeutics
generate ECM changes, and (iii) knowledge of how the ECM can alter CEnC function. These tools and
knowledge will be valuable for the study of FECD development and drug discovery.

## Key facts

- **NIH application ID:** 10874016
- **Project number:** 1R01EY034906-01A1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Sangita Patel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $358,400
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874016

## Citation

> US National Institutes of Health, RePORTER application 10874016, Corneal Endothelium – Extracellular Matrix Interactions (1R01EY034906-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10874016. Licensed CC0.

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