# The control of retinal vascular development by Norrin and Frizzled4

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $357,384

## Abstract

Project summary
 Retinal vascular diseases are major causes of vision loss in the United States and
around the world. Age-related macular degeneration, diabetic retinopathy, and retinopathy of
prematurity are all associated with the growth of new blood vessels (neovascularization) into or
on the surface of the retina. They are also associated with the leakage of fluid from the retinal
blood vessels into the retina (edema) and with bleeding from new vessels. To better treat these
disorders, we need to understand the signaling pathways that control the growth and integrity of
retinal blood vessels. Over the past decade we have characterized a signaling system that
controls the growth and barrier properties of retinal blood vessels. In this pathway, Norrin, a
ligand synthesized by Muller glia, activates canonical Wnt signaling via its receptor [Frizzled4
(Fz4)], co-receptor (Lrp5), and co-activator (Tspan12) on the surface of vascular endothelial
cells (ECs). In humans and mice, mutations in any of the genes coding for these proteins
impairs retinal vascular development.
 The objectives of this proposal are to develop and apply new molecular technologies
and genetically engineered mouse models to: (1) identify novel protein regulators of Norrin/Fz4
signaling and determine their roles in retinal vascular development and homeostasis, (2) define,
on a whole-genome scale, the transcriptional and chromatin responses of vascular ECs to
Norrin/Fz4 signaling, (3) discover and characterize cell surface and secreted proteins that
mediate communication between vascular ECs and their pericyte and astrocyte neighbors, and
(4) develop and characterize reporter mouse lines that permit simultaneous, cell-type-specific,
and cellular resolution analyses of the activities of two or more signaling pathways, and then
apply these lines to the analysis of signaling (including Norrin/Fz4 signaling) in developing,
adult, and diabetic vascular ECs.
 As the retinal vasculature is very similar between mice and humans, and the Norrin/Fz4
pathway (as well as other signaling pathways such as VEGF, Notch, and TGF-beta) are highly
conserved across mammals, the proposed experiments with mice should translate directly to
humans. Finally, the new technologies and mouse lines that will be developed in the proposed
studies will be freely disseminated to the scientific community and should have a catalytic effect
on the field.

## Key facts

- **NIH application ID:** 10197131
- **Project number:** 5R01EY018637-14
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** JEREMY NATHANS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,384
- **Award type:** 5
- **Project period:** 2008-01-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197131

## Citation

> US National Institutes of Health, RePORTER application 10197131, The control of retinal vascular development by Norrin and Frizzled4 (5R01EY018637-14). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10197131. Licensed CC0.

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