# Molecular Dissection of the Axonal Injury Response for Regeneration and Neuroprotection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $368,138

## Abstract

The axonal connections between neurons are essential for their proper function. Disruption of these connections
in insults ranging from spinal cord injury to glaucoma to chemotherapy-induced neuropathy are frequently
debilitating. Whereas intrinsic capacity for axon regeneration offers hope for recovery in the PNS, its failure in
the CNS, along with injury-induced neurodegeneration, frequently results in permanent deficits. Our lab aims to
understand how neurons respond to axon injuries, with the goal of modulating this response for improved axon
regeneration and neuronal survival. In the current proposal, we capitalize on our recent discovery of an
unexpected second branch of the axonal injury response, a pathway that is also implicated in normal memory
formation and in neurodegenerative diseases. Understanding the impact of this pathway, known as the
Integrated Stress Response (ISR), on repair and survival in the tractable models of PNS and CNS axonal injury
may facilitate ISR-based therapies currently being explored for a variety of conditions. Previously, we and others
have demonstrated that both axon regeneration and neurodegeneration depend on a master regulator of the
axonal injury response known as the Dual Leucine-zipper Kinase (DLK). Injury-induced DLK activation leads to
a multifaceted transcriptional response, primarily through the initiation of a well-known MAP kinase (MAPK)
signaling cascade. Unexpectedly, we recently discovered that DLK is also necessary and sufficient to engage
the ISR. How do the MAPK and ISR branches of the DLK response interact to define the differential apoptotic
and regenerative fates of injured neurons in the CNS and PNS? Our ongoing efforts to address this question
have converged on one of the principal downstream effectors of the ISR, the Activating Transcription Factor 4
(ATF4), as a potential regulator of both regeneration and apoptosis. Our preliminary evidence suggests that
ATF4 may differentially impact regenerative potential in the CNS and PNS. In parallel, we have found that
inhibition of the ISR reduces neurodegeneration in a CNS model, though it is not yet known whether this results
from reduced ATF4 or from other aspects of the ISR. To understand the role of ATF4 within the ISR and within
the broader DLK response, we propose to combine in vitro approaches with in vivo CNS and PNS injury models.
First, to understand neuroprotection by ISR inhibition, we will determine the specific contribution of ATF4 to gene
expression changes and neuronal loss in the CNS in vivo. Secondly, we will test the in vivo roles of the ISR and
ATF4 in axon regeneration following peripheral nerve injury and following optic nerve injury, the latter in
combination with manipulations that partially overcome CNS regenerative failure. Thirdly, to discover
mechanisms by which ATF4 regulates axon regeneration, we will test the genetic interactions of ATF4 with its
putative binding partners, upstream mediators, and downstream tar...

## Key facts

- **NIH application ID:** 10909379
- **Project number:** 5R01NS112691-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Trent Watkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $368,138
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909379

## Citation

> US National Institutes of Health, RePORTER application 10909379, Molecular Dissection of the Axonal Injury Response for Regeneration and Neuroprotection (5R01NS112691-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909379. Licensed CC0.

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