# Targeting aging genes and pathways to promote optic nerve regeneration

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

## Abstract

Summary
To date, targeting the genes regulating intrinsic axon growth ability have produced by far the most promising
results in optic nerve regeneration. Recent studies, including ours, have provided strong evidence that neuronal
aging might be a key converging process underlying the loss of intrinsic axon growth ability of CNS neurons.
Indeed, many genes that act to regulate axon regeneration are also hallmark genes of aging (genomic instability,
telomere attrition, epigenetic alteration, and nutrient sensing, etc.). First, recent studies and our preliminary
results showed that c-Myc and p53, two well-known genes involved in DNA repair and genomic instability during
aging, act to support optic nerve regeneration. Second, our preliminary study showed that telomerase reverse
transcriptase (TERT) was necessary for sensory axon regeneration in vivo. Third, aging is often associated with
decreased methylation of histone 3 at lysine 27 (H3K27) and increased methylation of H3K4, resulting in reduced
amount of heterochromatin. In support, the level of H3K27 demethylase UTX increases during aging and
knocking out UTX in c. elegans promotes longevity. Our unpublished study showed that knocking out UTX and
its targeted gene, Magi3, in RGCs drastically promoted optic nerve regeneration. Fourth, the insulin and IGF-1
signaling (IIS) pathways, the key regulators of nutrient sensing, are the most conserved aging controlling
pathway in evolution. IGF-1 and many IIS downstream targets, such as Pten/PI3K, Akt, and mTor, are all
important regulators of optic nerve regeneration. Our published study and a recent study have shown that Sirt1
and LKB1, two important nutrient sensors, function to regulate sensory axon and spinal cord regeneration,
respectively. Foxo3, another key target of Akt signaling, has recently been shown to promote vascular cell
regeneration through Sirt1. Lastly, recent findings indicated that cellular reprogramming process can reverse
aging and rejuvenate the cells. Importantly, manipulations of several reprogramming factors, such as KLF4 and
Lin28, have been shown to promote optic nerve regeneration. Therefore, we hypothesize that aging regulatory
genes/pathways can be manipulated to promote optic nerve regeneration through rejuvenation of mature CNS
neurons. In Aim 1, we will determine if manipulation of miR-138/Sirt1, TERT, and Foxo3 in RGCs can promote
optic nerve regeneration. In Aim 2, we will first determine if combination of these aging genes with myosin II
knockout or enhanced neural activity would have synergistic effects on regeneration. We will then use RNA-seq
and ATAC-seq of purified RGCs to explore how these aging genes regulate optic nerve regeneration. In Aim 3, by
performing RNA-seq and ATAC-seq of purified RGCs at different developing, maturation, and aging stages, we
will first use advanced integrative bioinformatics analyses to identify top candidate aging genes and their
associated transcription factors, both of which act...

## Key facts

- **NIH application ID:** 10075934
- **Project number:** 5R01EY030883-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Fengquan Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,093
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075934

## Citation

> US National Institutes of Health, RePORTER application 10075934, Targeting aging genes and pathways to promote optic nerve regeneration (5R01EY030883-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10075934. Licensed CC0.

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