# G protein-coupled receptor regulation of transcriptional mechanisms in the retinal vasculature.

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $461,082

## Abstract

PROJECT SUMMARY
Retinal vascular dysfunction leads to visual impairment and loss of vision, a phenomenon that occurs in
retinopathy of prematurity (ROP), diabetic retinopathy (DR) and neovascular age-related macular degeneration
(AMD). Injury of the retinal endothelial cell (REC) initiates a series of pathogenetic events that ultimately lead
to accelerated progression of retinal diseases. How REC injury leads to transcriptional changes that determine
whether the retinal vascular function is restored or leads to pathological changes is not known. Sphingosine
1-phosphate (S1P), a blood-borne lipid mediator that signals via G protein-coupled S1P receptors (S1PR1-5).
The applicant’s laboratory discovered the first S1PR and worked out its functional roles in vascular barrier
maintenance, development/ maturation, anti-inflammatory processes, cell survival and endothelial/ pericyte
interactions. Although two FDA-approved S1PR-targeted drugs are efficacious in the treatment of multiple
sclerosis, retinal blistering and macular edema are dose-limiting adverse effects due to the impairment of
retinal barriers. We recently showed that S1PR signaling suppresses vascular endothelial growth factor
(VEGF)-induced AP-1 transcription factor activity and permits Norrin/Wnt/ß-catenin-dependent REC gene
expression, thus leading to retinal REC specialization. Among the AP-1 factors, JunB protein expression is
most prominently regulated by S1PR signaling, an event needed for optimal vascular network expansion and
formation of deep retinal vascular plexus. The central hypothesis of the proposal is that REC S1PR signaling
establishes JunB transcription factor gradients and permits the REC organotypic specialization mechanisms.
In this manner, attenuated S1PR signaling axis drives poorly functional retinal vascular network and
vasoproliferative ROP. In this proposal, the first specific aim will elucidate mechanisms and consequences of
S1PR sculpting of JunB transcription factor gradients in REC. Second, how S1PR signaling in the REC
promotes organotypic specialization by enabling efficient Norrin/Wnt/ß-catenin-dependent signal transduction
and gene expression will be conducted. Specific focus will be on omega-3 fatty acid transporter (MFSD2A) and
iron transporter (TFRC). The relevance of these mechanisms in the mouse models of ROP will be addressed
in specific aim 3. These studies are anticipated to enhance our understanding of basic mechanisms of retinal
vascular development, specialization and disease in the retina and ultimately lead to approaches that tame
retinal disorders by targeting the S1P lipid signaling axis and to provide S1PR inhibitors with fewer side effects.

## Key facts

- **NIH application ID:** 10390409
- **Project number:** 5R01EY031715-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Timothy Tun Hla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $461,082
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390409

## Citation

> US National Institutes of Health, RePORTER application 10390409, G protein-coupled receptor regulation of transcriptional mechanisms in the retinal vasculature. (5R01EY031715-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10390409. Licensed CC0.

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