# In vivo Visualization of Delayed Wallerian Degeneration in Peripheral Nerve Injury

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2024 · $194,375

## Abstract

SUMMARY
Peripheral nerve injuries are common and debilitating conditions affecting more than one hundred thousand
people annually in the United States. Prognosis for recovery of severe nerve injuries is poor, as high-grade
axonotmetic and neurotmetic injuries usually do not spontaneously recover. These injuries require surgical
intervention and if the nerve injury is located far from the target muscles, nerve repairs fail to provide useful
function in half of patients- leading to permanent physical disabilities and enormous emotional stress. To improve
clinical outcomes, a better understanding of the molecular mechanisms involved in nerve injury is critical. The
traditional view that Wallerian degeneration (WD) is inevitable after nerve injury has recently been challenged
with the discovery of the role of nicotinamide adenine dinucleotide (NAD) in supporting maintenance of viable
axons. SARM1 with its NADase enzymatic activity, has been identified as a key gatekeeper of WD. After a severe
nerve injury, SARM1 rapidly degrades NAD resulting in catastrophic structural changes to the distal axon.
Blockade of this phenomenon, combined with the promise of fusogens can provide a potential mechanism for
transected nerves to rapidly recover after injury. Optical imaging with its high spatial and temporal resolution is
highly promising to visualize the entire process in the nerve tissue, however high scattering from the skin and
other adjacent organs limit the application to only in vitro or ex vivo studies. To address these limiting issues, we
developed a minimally invasive in vivo model that enables continuous imaging of a peripheral nerve injury with
a high, single axon resolution. Our approach uses a flexible skin-embedded transparent optical window with the
nerve surgically repositioned above the muscle layer. This modality allows daily or even hourly, longitudinal
imaging of the nerve with virtually any optical reporter that can be used in living animals. When combined with
fluorescent reporters and a high-resolution imaging system (i.e., two-photon imaging), this method generates a
3D view of the nerve with unprecedented resolution. In Aim 1 we will develop a double transgenic mouse reporter
model (THY-1/CFP and S100/GFP) expressing different levels of SARM1 (SARM1-/-, SARM1-/+, SARM1+/+). We
will then monitor differences in the degree and timing of axonal degeneration after a unilateral sciatic nerve injury,
using our optical window. In Aim 2, we will synthesize a library of small activatable fluorogenic probes that mimic
NAD+ to directly measure the activity of SARM1 in the distal stump. Overall, this imaging approach will provide
direct visualization of the morphologic and metabolic characteristics of the distal stump degeneration in live
animals. It will also establish a conceptual framework for future investigation of the fundamental processes
during nerve regeneration. This approach will lead to new discoveries in the biology of these processe...

## Key facts

- **NIH application ID:** 10898207
- **Project number:** 1R21NS135646-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Mikhail Y. Berezin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,375
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898207

## Citation

> US National Institutes of Health, RePORTER application 10898207, In vivo Visualization of Delayed Wallerian Degeneration in Peripheral Nerve Injury (1R21NS135646-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10898207. Licensed CC0.

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