# Reprogramming retinal ganglion cells for optic nerve regeneration and guidance

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $397,093

## Abstract

There are 3 major goals for successful optic nerve regeneration and functional recovery: 1) identify
more genes that can be manipulated to promote optic nerve regeneration via different mechanisms, 2) identify
the optimal combinatory approaches that can promote sufficient regenerating axons from different subsets of
retinal ganglion cells (RGCs) to cross the optic chiasm and reach the brain, and 3) precisely guiding regenerating
optic nerve axons from different types of RGCs to their original brain targets. The goal 3 is the most difficult one
whereas the goal 1 and 2 are the prerequisites to achieve goal 3. The overall goal of this study is to mainly
address the first 2 goals. KLF4 and c-Myc, two factors used for the induced pluripotent stem cells (iPSCs)
reprogramming, were shown to be important regulators of optic nerve regeneration. The preliminary study
showed that overexpression of reprogramming factor Lin28 in mouse RGCs also drastically promoted optic nerve
regeneration. A recently completed but unpublished study showed that H3K27 methylation is necessary and
sufficient for sensory axon regeneration in vivo by suppressing KLF4. Knocking out the demethylase UTX in
RGCs dramatically enhanced optic nerve regeneration. Because H3K27 methylation and associated histone
methyltransferase and demethylases have been shown to work together with reprogramming factors during iPSC
process by modifying chromatin structure, we hypothesize that mature mouse RGCs can be reprogrammed
into a regenerating state via remodeling their epigenetic landscape through reprogramming factors or chromatin
modulators. In support, ChIP-seq analysis of H3K27me3 in regenerating neurons identified Magi3, a membrane
associated guanylate kinase, as a gene suppressed by H3K27me3. Deleting Magi3 in sensory neurons or RGCs
led to marked sensory axon and optic nerve regeneration, respectively. Besides Magi3, many cell reprogramming
factors, such as Oct4, FoxA1/2, GATA3/4, PAX6, were identified as top candidate genes regulated by H3K27me3
in regenerating neurons. Therefore, in Aim 1, the study will investigate the roles and mechanisms by which
Lin28 and Magi3 regulate optic nerve regeneration. Preliminary study demonstrated that deleting myosin IIA/B
in RGCs by itself could promote optic nerve regeneration and abolish backward turning of regenerating axons
when combined with Pten deletion. Enhanced RGC neural activity, when combined with mTOR activation, could
induce long distance optic nerve regeneration. Thus, in Aim 2, the study will determine if combination of genetic
reprogramming with 2 mechanistically different approaches, cytoskeletal modulation or neural activity, can lead
to more efficient optic nerve regeneration into the brain. In Aim 3, the study will investigate the potential roles
of novel cell reprogramming genes mentioned above in regulation of optic nerve regeneration. The proposed
study is based on very strong preliminary data. The results will open a new direct...

## Key facts

- **NIH application ID:** 10203993
- **Project number:** 5R01EY027347-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xu Cao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,093
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10203993

## Citation

> US National Institutes of Health, RePORTER application 10203993, Reprogramming retinal ganglion cells for optic nerve regeneration and guidance (5R01EY027347-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10203993. Licensed CC0.

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