# Cellular and molecular mechanisms of retinoic acid-mediated blood-retinal barrier regulation

> **NIH NIH F32** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $69,306

## Abstract

PROJECT SUMMARY
The blood-retinal barrier (BRB) mediates movement of molecules from the blood to the retina,
protecting the retinal neural tissue from potentially harmful molecules and maintaining retinal
homeostasis. Breakdown of the BRB is associated with ocular diseases such as diabetic retinopathy
and age-related macular edema. The BRB consists of both an inner barrier, formed by microvascular
endothelial cells, and an outer barrier, formed by the RPE. Tight junctions between these cells are
essential to barrier function. However, the molecular mechanisms regulating tight junction integrity in
the BRB and the effects of BRB breakdown on retinal morphology and visual function are not fully
understood. The zebrafish (Danio Rerio) is an ideal model to investigate the mechanisms of BRB
breakdown and maintenance due to its rapid ex vivo visual development and the availability of a wide
array of genetic tools. We have recently determined that retinoic acid (RA), a metabolite of Vitamin A,
plays a critical role in the maintenance of the BRB. Disruption of RA signaling in zebrafish larvae and
adults with a pan-retinoic acid receptor inhibitor (BMS493) results in BRB breakdown, disrupted
expression of tight junction proteins in the retinal vasculature and RPE, and decreased visual acuity.
Preliminary RNA sequencing and pathway analysis of differentially expressed genes indicates that
the mTOR signaling pathway is significantly upregulated in retinas of fish treated with an inhibitor of
RA signaling compared to untreated fish. Additionally, inhibition of mTOR signaling by treatment with
rapamycin is sufficient to restore BRB integrity in RA-inhibitor-treated larvae. Therefore, we propose
that RA maintains the BRB via crosstalk with the mTOR pathway and that RA-inhibitor-induced BRB
breakdown leads to retinal damage and visual dysfunction. We will characterize the role of RA and
the mTOR signaling pathway in BRB maintenance by assessing the pattern of mTOR activation in the
inner and outer BRB and identifying the upstream and downstream regulators involved in BMS493-
induced BRB breakdown. We will also determine which cells in the retina contribute to RA-inhibitor-
induced BRB breakdown and characterize the cellular changes in the retina in response.
Understanding the cellular and molecular mechanisms involved in RA-mediated BRB maintenance
and the progression of retinal damage and vision loss following BRB breakdown will be critical to
identify therapeutic approaches for preventing vision loss due to BRB disruption.

## Key facts

- **NIH application ID:** 9953812
- **Project number:** 5F32EY029147-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** LANA Mary POLLOCK
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2019-04-11 → 2022-04-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953812

## Citation

> US National Institutes of Health, RePORTER application 9953812, Cellular and molecular mechanisms of retinoic acid-mediated blood-retinal barrier regulation (5F32EY029147-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9953812. Licensed CC0.

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