# MECHANISMS OF CHROMATIN REMODELING PROMOTING AXON REGENERATION

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $333,594

## Abstract

ABSTRACT
 Lack of robust axonal regeneration represents a major barrier to functional recovery following injury to
neurons within the central nervous system (CNS). In contrast, peripheral neurons can regenerate after injury.
Activation of a pro-regenerative growth program in peripheral neurons relies on the expression of
regeneration-associated genes (RAGs) that allow for robust axonal re-growth. Although several genes have
been identified for their pro-regenerative influence, individual gene based approaches have yielded limited
success in axon regeneration, illustrating that manipulation of individual RAGs is unlikely to be sufficient to
stimulate robust long-distance axon regeneration in the injured CNS. Therefore, understanding how a large
ensemble of RAGs can be simultaneously activated after injury could reveal strategies to initiate the
transcriptional pro-regenerative program. Epigenetic regulations, which include modification of the chromatin,
affect combinations of multiple genes and hence represent ideal strategies to promote neural repair. Our goal
is to gain new insights into the molecular events that regulate chromatin function in response to injury in
peripheral neurons, and identify potential targets for future treatment of CNS injuries
 We previously demonstrated that axon injury elicits an epigenetic switch stimulating the regenerative
competence of sensory neurons. Specifically, we discovered that calcium wave back-propagating from the
site of axonal injury increases histone acetylation levels, stimulating the regenerative competence of sensory
neuron. This work demonstrates a link between axon injury and chromatin remodeling and suggests that a
coordinated pro-regenerative program is initiated by changes in the epigenetic landscape. In our recent
studies, we identified hypoxia-inducible factor 1α (HIF-1α) as an important factor regulating axon
regeneration via epigenetic as well as transcriptional regulatory mechanisms. We found that HIF-1α is
required in injured sensory neurons to increase histone acetylation levels, to stimulate the expression of pro-
regenerative genes and to promote axon regeneration. In mice breathing repeatedly low oxygen levels for
brief periods (i.e., acute intermittent hypoxia, AIH) we observed increased levels of HIF-1α and enhanced
axon regeneration in sensory neurons. However, the signaling pathways in normoxic conditions regulating
HIF-1α accumulation and the precise mechanisms by which HIF-1α regulates chromatin in injured neurons
remain elusive. Here we propose to uncover the molecular mechanisms controlling HIF-1α stability and
activity following injury and to establish its specific roles in chromatin remodeling in injured neurons. We will
also test if AIH can recapitulate at least in part the epigenetic changes elicited by peripheral axon injury and
activate a pro-regenerative program in both peripheral and central neurons. This proposal has the potential to
provide further rationale for the i...

## Key facts

- **NIH application ID:** 9934288
- **Project number:** 5R01NS096034-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Valeria Cavalli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,594
- **Award type:** 5
- **Project period:** 2016-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934288

## Citation

> US National Institutes of Health, RePORTER application 9934288, MECHANISMS OF CHROMATIN REMODELING PROMOTING AXON REGENERATION (5R01NS096034-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9934288. Licensed CC0.

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