# Cellular and molecular analysis of spontaneous optic nerve regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $525,124

## Abstract

In humans, vision is the most important sense and damage to the retina or the optic nerve can cause
irreversible vision loss. This is because the retina and the optic nerve are part of the central nervous system
(CNS), which in adult mammals has lost its regenerative capacity. In rodents, several neuron intrinsic signaling
pathways have now been identified that majorly boost axonal growth of injured retinal ganglion cells (RGC)
axons, yet this has come with the realization that enhanced axonal regrowth frequently results in extensive
misguidance, detrimental to function regeneration. Currently, the identity of extrinsic guidance cues, the
mechanisms by which they direct regenerating RGC axons, and the identity of glia and other cell types along
the optic nerve path that provide guidance are not well understood. Surprisingly, even the cellular behaviors of
resident glial cells and immune cells summoned to the injury site, and how they interact with regenerating RGC
axons is not well understood, mainly due to challenges of live cell imaging in mammals. In contrast to
mammals, amphibians and fish, including zebrafish, have retained a remarkable capacity for optic nerve
regeneration. We have established a powerful assay to transect the optic nerve in larval zebrafish, and monitor
axonal and functional regeneration. RGC axons regenerate within a few days independently of neurogenesis,
providing a unique opportunity to study the genes critical for spontaneous regeneration independently of the
confound of neural survival and neurogenesis. From a genetic screen we identified mutants in two genes, the
glycosyltransferase lh3 and one of its substrate col18a1 critical for the guidance of injured RGC axons. Our
preliminary data support a hypothesis by which lh3 and col18a1 participate in a pathway to provide extrinsic
guidance –likely by surrounding glia- to guide regenerating RGC axons towards the CNS midline. The goal of
this proposal are to define fundamental behaviors of regenerating axons, glia and immune cells in their native
environment, and to determine the cellular and molecular mechanism by which lh3 and Col18a1 guide
regenerating optic nerve axons. The experiments in this proposal will: (1) reveal and define for the first time in
any vertebrate system the fundamental behaviors of regenerating optic nerve axons, glia and immune cells in
their native environment; (2) determine the cellular and molecular mechanisms by lh3 and col18a1 direct optic
nerve regeneration; and (3) determine how col18a1 function connects to axonal guidance of RGC axons.
These studies are relevant to the study of human diseases that cause damage to the optic nerve, including
hereditary optic neuropathies and glaucoma. Although spontaneous optic nerve regeneration is largely absent
in mammals, boosting axonal regeneration via neuron intrinsic manipulation frequently results in misguidance,
underscoring the importance to define the cellular interplay of injured RGC axons with s...

## Key facts

- **NIH application ID:** 10450086
- **Project number:** 5R01EY024861-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Granato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $525,124
- **Award type:** 5
- **Project period:** 2014-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450086

## Citation

> US National Institutes of Health, RePORTER application 10450086, Cellular and molecular analysis of spontaneous optic nerve regeneration (5R01EY024861-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450086. Licensed CC0.

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