# Cellular and Molecular Mechanisms of Retinal Fibrosis

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $426,903

## Abstract

PROJECT ABSTRACT
Retinal neovascular disorders, such as retinopathy of prematurity and diabetic retinopathy, are the most
common causes of vision loss of working age adults and infants. Vascular endothelial growth factor
(VEGF) inhibitors have transformed the treatment of these disorders and resulted in improved outcomes
for millions of patients worldwide. However, regression of neovascularization often leads to deposition
of a fibrotic scar on the surface of the retina. These pre-retinal fibrotic scars can contract, resulting in
distortion of the retinal surface or detachment of the neurosensory retina. To date, surgery is the only
available intervention, often with poor visual outcomes. Despite the importance, very little is known
about the molecular mechanisms that regulate the formation of this pathological tissue, and there is
debate on the cellular source of fibrotic scar tissue in the retina. One of the main roadblocks for making
progress in this field is the lack of a robust and reproducible mouse model to study and manipulate pre-
retinal fibrosis, in order to decipher the key cellular and molecular mechanisms that regulate this
process. We have developed a novel mouse model of severe retinopathy of prematurity that develops
pre-retinal fibrosis subsequent to hypoxia driven neovascularization. Using histology and single cell
sequencing, our preliminary data indicates that the pre-retinal fibrotic scar results from pericytes that
upregulate collagen I expression following neovascularization. Here, we propose to further understand
the mechanism of pre-retinal scar formation by characterizing and manipulating this novel model. First,
we will fully characterize this model examining the time course of fibrotic scar formation, vaso-
obliteration, neovascularization, retinal inflammation, and visual function. Second, using lineage tracing
and single cell sequencing we will determine the identity the critical collagen I producing cells. Third,
we propose to test the hypothesis that activation of TGFβ signaling in pericytes is the key driver of pre-
retinal fibrosis. Our goal in understanding the cellular and molecular origin of retinal fibrosis is to
develop novel therapeutics to prevent blindness from traction in advanced ischemic retinopathies.

## Key facts

- **NIH application ID:** 10819024
- **Project number:** 1R56EY032513-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Eric D Nudleman
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $426,903
- **Award type:** 1
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819024

## Citation

> US National Institutes of Health, RePORTER application 10819024, Cellular and Molecular Mechanisms of Retinal Fibrosis (1R56EY032513-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10819024. Licensed CC0.

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