# Norrin Signaling in the Retina: Regulation of the Blood-Retina Barrier

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $440,431

## Abstract

Our overall objective is to understand the role of norrin/frizzled4 signaling as regulator of the blood-retina
barrier (BRB) in human disease, using mice as model system. Impairment of the BRB causes edema and is
associated with diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, familial
exudative vitreoretinopathy (FEVR), and uveitis. BRB induction and maintenance are controlled by the critical
b-catenin-dependent (canonical) norrin/frizzled4 signaling pathway. Disrupted norrin/frizzled4 signaling causes
FEVR. How the impairment of norrin/frizzled4 signaling causes pathological changes, how the pathway is
regulated under stress, and if activation of norrin/frizzled4 signaling is a valid therapeutic approach to restore
BRB dysfunction, are all not understood. These knowledge gaps need to be addressed to exploit the enormous
basic research progress on norrin/frizzled4 signaling for therapeutic intervention. Aim1: We showed that
endothelial cell-specific inactivation of norrin signaling in developed mice provides a new model to study
pathological consequences of BRB breakdown. The new model does not display compound pathologies
observed in existing models of BRB disruption characterized by pericyte defects, perfusion defects, and
hypoxia, allowing us to study pathological consequences of BRB defects per se. Endothelial cell-specific
disruption of norrin/frizzled4 signaling in developed mice causes immunoglobulin extravasation, complement
activation, cystoid edema, and reduced b-wave in electroretinography (ERG). We will use mouse genetics to
test the role of the classical complement pathway in mediating long-term pathological consequences of BRB
breakdown in an otherwise intact vasculature. Fluorescein angiography and ERG will be performed at multiple
time points, and histopathology at the 1-year end-point. Successful completion of this aim will determine roles
of the classical complement pathway in retinal disease beyond the known roles in age-related macular
degeneration. Aim2: Preliminary data show that increased levels of a stress sensor protein in endothelial cells
strongly inhibit canonical signaling and negatively regulate BRB function. We will use conditional mouse
genetics to activate the stress sensor in endothelial cells, determine BRB function, and test for genetic
interactions with increased or reduced levels of b-catenin signaling. Cell-based assays will be performed to
determine the mechanistic basis of this powerful regulation. Successful completion of this aim will provide
novel insights into the regulation of the BRB under stress. These mechanisms may be exploited for modulating
the BRB, e.g., in the context of restoring the barrier in disease, or for drug delivery. Aim3: Current efforts to
target norrin/frizzled4 signaling for therapeutic intervention have focused on anti-angiogenesis approaches in
proliferative retinopathies. We will determine if the activation of b-catenin in endothelial cells r...

## Key facts

- **NIH application ID:** 10475728
- **Project number:** 5R01EY024261-09
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Harald Junge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $440,431
- **Award type:** 5
- **Project period:** 2014-04-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475728

## Citation

> US National Institutes of Health, RePORTER application 10475728, Norrin Signaling in the Retina: Regulation of the Blood-Retina Barrier (5R01EY024261-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10475728. Licensed CC0.

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