# Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $323,875

## Abstract

SUMMARY: Diseases resulting in degeneration of the retinal pigment epithelium (RPE) are among the leading
causes of blindness worldwide and no therapy exists that can replace RPE or restore lost vision. Age-related
macular degeneration (AMD) is one such disease and is the third leading cause of blindness in the world.
While there are some effective treatments for exudative (wet) AMD, ~90% of AMD cases are atrophic (dry) and
these are currently untreatable. Transplantation of stem-cell derived RPE has emerged as a possibility for
treating geographic atrophy and clinical trials are underway. However, little is known about the fate of
transplanted RPE and whether their survival and integration can be improved. An intriguing alternative
approach to treating AMD and other RPE diseases is to develop therapies focused on stimulating endogenous
RPE regeneration. For this to be possible, we must first gain a deeper understanding of the mechanisms
underlying RPE regeneration. In mammals, RPE regeneration is extremely limited and in some contexts RPE
cells overproliferate after injury, such as during proliferative vitreoretinopathy, where proliferative RPE cells
invade the subretinal space and lead to blindness. Recently, a subpopulation of quiescent human RPE stem
cells was identified that can be induced to proliferate in vitro and differentiate into RPE or mesenchymal cell
types, suggesting that the human RPE contains a population of cells that could be induced to regenerate.
 Despite these studies, little is known about the process by which RPE cells respond to injury to elicit a
regenerative, rather than pathological, response. Indeed, no studies have demonstrated regeneration of a
functional RPE monolayer following severe RPE damage in any model system. The development of such a
model is a critical first step to acquiring a deeper understanding of the molecular mechanisms underlying RPE
regeneration. This knowledge gap is a major barrier to developing effective strategies to restore RPE lost to
disease or injury and is the focus of our proposal. We developed a transgenic zebrafish model to study RPE
injury and regeneration and demonstrate that the zebrafish RPE regenerates after severe injury. We further
demonstrate i) that RPE regeneration involves a robust proliferative response during which proliferative cells
move to the injury site and differentiate into RPE, ii) that the source of regenerated cells is likely uninjured
peripheral RPE, iii) using this system, we can identify the molecular underpinnings of the regenerative
response, and iv) the innate immune system plays a critical role in RPE regeneration. Experiments in this
proposal build off of these strong preliminary data to test the hypothesis that RPE regeneration is effected by a
population of injury-activated resident RPE cells that proliferate upon injury and regenerate lost RPE tissue.
Understanding how injury-responsive RPE cells proliferate in vivo and the signals/pathways active durin...

## Key facts

- **NIH application ID:** 9937721
- **Project number:** 5R01EY029410-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jeffrey Gross
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,875
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937721

## Citation

> US National Institutes of Health, RePORTER application 9937721, Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration (5R01EY029410-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9937721. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*