# Metabolic reprogramming of endothelial precursor cells in subretinal fibrosis

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $448,144

## Abstract

Therapeutic agents that target the vascular endothelial growth factor (VEGF) have achieved remarkable
success in patients with the neovascular form of age-related macular degeneration (nAMD). An emerging
clinical problem, however, is that many of the nAMD patients develop subretinal fibrosis (SRF) after receiving
anti-VEGF therapy. SRF can cause irreversible structural damage to the retina and is a major vision-
threatening complication with no effective treatment. The disease mechanisms of SRF in nAMD are largely
unknown. Transforming growth factor beta (TGF-beta) is a major driver of fibrosis. The source of TGF-beta in
SRF, and its main effector cells, have not been well defined. SRF can be modeled in mice with spontaneous or
experimentally-induced choroidal neovascularization (CNV). In our published and preliminary studies, we found
that mice with targeted deletion in the very low-density lipoprotein receptor (Vldlr) gene developed SRF when
their CNV lesions regressed. Using single cell RNA sequencing, we identified endothelial precursor cells
(EPCs) as a major cluster of cells that displayed markers of fibrosis. Similar findings were observed in JR5558
mice and in laser-induced CNV. EPCs have stem cell-like properties, and they are recruited to the choroidal
and retinal neovessels to facilitate the vascular repair. In the subretinal microenvironment, EPCs gradually lose
their cellular structures and transdifferentiate into fibroblast-like cells. We hypothesize that TGF-beta-mediated
metabolic reprograming of EPCs is a key signaling event that contributes to the formation and progression of
SRF after CNV. For the project proposed in this application, we will determine the roles of EPCs in mouse
models of CNV and in human donor eye tissues with wet AMD. We will also examine the metabolic
reprogramming of EPCs in response to TGF-beta. Furthermore, we will explore whether Muller cell-derived IL-
33 promotes TGF-beta production from macrophages, and whether inhibiting the IL-33 signaling suppresses
SRF. Results from these studies will reveal novel molecular and cellular mechanisms of SRF, and define new
targets for potential therapeutic intervention.

## Key facts

- **NIH application ID:** 10916478
- **Project number:** 5R01EY034742-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** JIYANG CAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $448,144
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916478

## Citation

> US National Institutes of Health, RePORTER application 10916478, Metabolic reprogramming of endothelial precursor cells in subretinal fibrosis (5R01EY034742-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10916478. Licensed CC0.

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