# Wnt signaling-mediated control of blood-retinal barrier

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $429,225

## Abstract

Project Summary
Breakdown of the inner endothelial blood-retinal barrier (BRB) is a major cause of retinal edema and resultant
vision loss in vascular eye diseases. In addition to paracellular transport though the tight junctions between
endothelial cells (ECs), transportation of substance, particularly large molecules, also occurs through
transcellular vesicles (transcytosis) across ECs. Normal healthy blood vessels in the central nervous system,
including retinas, display low rates of transcytosis essential for maintaining blood-brain barrier (BBB) and inner
BRB. Yet molecular mechanisms governing retinal EC transcytosis are poorly understood, which considerably
limits our ability to manipulate inner BRB to treat vascular eye disease. In this project we identified that Wnt
signaling pathway, a pathway fundamentally important for angiogenesis and vascular integrity control, may act
as a critical negative regulator of EC transcytosis to maintain inner BRB. Mutations in the inter-related Wnt
signaling pathway involving the ligand Norrin, and the receptor Frizzled4 and co-receptor low density
lipoprotein receptor-related protein 5 (LRP5) are linked with development of familial exudative vitreoretinopathy
(FEVR) and Norrie disease, both with inner endothelial BRB breakdown. Activation of canonical Wnt signaling
involves stabilization of β-catenin, which then translocates to the nucleus to bind nuclear T-cell factor /lymphoid
enhancer factor (TCF/LEF) to influence target genes. Our preliminary data show that loss of Wnt signaling in
mouse models of FEVR and Norrie disease (Lrp5-/- and Norriny/- mice) significantly increased EC transcytosis,
with decreased levels of MFSD2a (major facilitator super family domain containing 2a), a membrane
transporter protein that suppresses EC transcytosis. We hypothesize that Wnt signaling is essential for
maintaining a low transcytosis rate in retinal EC critical for inner BRB integrity, through Mfsd2a-dependent
caveola vesicle modulation. We will test this hypothesis with three aims. In Aim 1 we will determine whether
Wnt signaling controls EC transcytosis by measuring vascular permeability of both small and large molecules
in Lrp5-/- and Norriny/- retinas, as well as in EC culture using transcytosis assay with Wnt modulation. In Aim 2
we will determine whether Wnt signaling regulates EC transcytosis through transcriptional regulation of
MFSD2a, a transcytotic inhibitor, using a combination of ex vivo and in vitro approaches. In Aim 3, we will
delineate whether Wnt signaling and MFSD2a control MFSD2a-assisted caveolar vesicle formation,
transportation, and exocytosis. This proposed work will uncover novel fundamental molecular mechanisms
governing EC transcytosis and inner BRB integrity, which is of significance in aiding development of improved
strategies to manipulate inner BRB. Findings from this work will also be highly relevant for modulation of BBB
in the central nervous system, as well as development of drug ...

## Key facts

- **NIH application ID:** 10147080
- **Project number:** 5R01EY028100-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** JING CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $429,225
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147080

## Citation

> US National Institutes of Health, RePORTER application 10147080, Wnt signaling-mediated control of blood-retinal barrier (5R01EY028100-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10147080. Licensed CC0.

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