# Traumatic Axonopathy in the CNS as Wallerian degeneration

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $461,693

## Abstract

PROJECT SUMMARY
In this application we propose that traumatic axonal injury (TAI) leads to an active axonopathy with the molecular
features of Wallerian degeneration and that targeting some of the relevant signals may protect axons as well as
brain systems. This hypothesis is based on recent findings in our laboratory showing that axonal breakdown
after diffuse TAI depends on the activation of Sterile Alpha and TIR Motif Containing 1 (SARM1) signaling and
that molecular interventions to block SARM1 lead to significant gains in preserving axons and rescuing
functions/behaviors that rely on axonal integrity. The case of TAI is unique in the sense that that many axons
are only partially injured and are potentially salvageable, therefore blocking Wallerian-type self-destruction may
afford long-term neuroprotection and change the prognosis of traumatic brain injury. Our proposal is organized
in three specific aims. In Aim 1 we establish that TAI in an index CNS tract, i.e. the corticospinal system, leads
to progressive axonopathy with the molecular signatures of Wallerian degeneration, i.e. activation of SARM1. In
Aim 2 we ask whether axonal protection by genetic or pharmacological blockade of SARM1 signaling in the
injured corticospinal tract translate into protection at the systems level, i.e. prevention of retrograde atrophy of
corticospinal neurons, preservation of corticospinal connectivity and rescue of CST-dependent motor skills. In
Aim 3 we explore the synergistic role of the mitogen-activated protein kinase (MAPK) pathway, specifically
signaling by the dual leucine zipper kinase (DLK) and related leucine zipper kinase (LZK), in corticospinal axonal
degeneration following TAI. The MAPK pathway signals general neuronal responses to injury and there is
evidence that specific members of the pathway cooperate with SARM1-related signals in triggering or affecting
the outcome of Wallerian degeneration. To achieve the previous aims, we use a complement of molecular
genetic tools including knockout mice, dominant negative strategies and genome editing with CRISPR-Cas9,
metabolomic assessments, CLARITY-based high-resolution neuropathology, structural and functional
connectivity markers, behavioral testing, and small molecules as probes for molecular targets and also as
therapeutic agents (the NAMPT inhibitor FK866 that serves as indirect inhibitor of SARM1 and the pan-Aurora
inhibitor tozasertib that blocks DLK/LZK signaling). In summary, here we explore specific molecular mechanisms
related to Wallerian degeneration and, in the course of doing this, we establish molecular targets for potential
pharmacological interventions in traumatic brain injury.

## Key facts

- **NIH application ID:** 10755663
- **Project number:** 5R01NS114397-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** VASSILIS E KOLIATSOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,693
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755663

## Citation

> US National Institutes of Health, RePORTER application 10755663, Traumatic Axonopathy in the CNS as Wallerian degeneration (5R01NS114397-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755663. Licensed CC0.

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