# Mechanisms of optic nerve regeneration

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $372,237

## Abstract

Degeneration of retinal ganglion cells (RGCs) and atrophy of their axons in the optic nerve are
hallmarks of many ocular diseases and result in permanent vision loss. There is a critical need for new
therapeutic strategies that induce robust axonal regeneration. The canonical Wnt/β3-catenin (“Wnt”)
signaling pathway is one of several different Wnt pathways that regulate axon growth in the developing
CNS. Although canonical Wnt ligands are known to be important for developmental axonal growth and
neuronal viability throughout the CNS, their role in RGC axonal growth in adults after optic nerve injury
is unknown. We recently demonstrated the novel finding that a single intravitreal injection of
recombinant canonical Wnt3a ligand led to significant axon regeneration after murine optic nerve crush
injury. In this project, we will ask whether repurposing the developmental axonal growth properties of
canonical Wnt ligands can be used as a potential therapeutic strategy for axonal regeneration after
optic nerve injury. Additionally, we will investigate how non-neuronal cells in the retina contribute to
optic nerve regeneration and whether they modulate the activity of pro-regenerative factors. We
demonstrated using a Wnt reporter transgenic mouse that Wnt3a-induced optic nerve regeneration was
associated with upregulated Wnt signaling in the Muller glia and RGC, suggesting that Wnt promotes
axonal regeneration by acting intrinsically within RGCs as well as extrinsically in non-RGCs such as
Muller glia. Our central hypothesis is that activation of Wnt3a signaling within the retina leads to axonal
regeneration, and that Wnt3a-induced axonal growth requires the involvement of Wnt signaling within
both RGC and Muller glia. In Aim 1, we will build upon our promising preliminary data and will test the
extent and duration of Wnt3a-induced axon regeneration after optic nerve crush in transgenic Wnt
reporter mice at the functional and morphological levels, will determine the amount and localization of
activated Wnt signaling and will identify underlying molecular mechanisms. In Aim 2, we will identify
cellular mechanisms of axonal growth by determining the contribution of RGCs and Muller glia to Wnt-
induced regeneration using cell-specific Wnt inhibitor and activator constructs. The collaborative team
of the PI, an expert on Wnt and Muller glia, Dr. Kevin Park, an expert on optic nerve regeneration, and
Drs. Ivanov and Porciatti, experts on RGCs, is uniquely suited to perform this study. This study will
have a high impact on the field by defining a novel pro-regenerative activity for Wnt3a on the optic
nerve, which will enhance the overall understanding of regeneration pathways and will identify novel
targets for RGC regrowth. These findings could be applied to developing new therapies for
regenerating damaged optic nerves, including traumatic injury, optic neuropathies, retinal ischemia and
late stage glaucoma.

## Key facts

- **NIH application ID:** 10146397
- **Project number:** 5R01EY026546-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Abigail S Hackam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,237
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146397

## Citation

> US National Institutes of Health, RePORTER application 10146397, Mechanisms of optic nerve regeneration (5R01EY026546-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10146397. Licensed CC0.

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