# Dissection of SARM1-Induced Axon Degeneration and Cell Death

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $598,620

## Abstract

Project Summary/Abstract:
 Axonal degeneration is an early and likely initiating event in some of the most prevalent neurological
diseases, including peripheral neuropathies, traumatic brain injury, Parkinson's disease and glaucoma.
Although axon loss is central to many neurological disorders, no treatments currently exist that effectively
target axonal breakdown. Axon degeneration is a subcellular self-destructive process that is activated by
traumatic, metabolic, and neurodegenerative insults. Conceptually this degeneration program is akin to the
apoptotic pathway—it is a biochemical pathway that dismantles injured axons in much the same way that the
apoptotic pathway orchestrates the programmed death of dysfunctional cells, although the molecular
mechanisms are primarily distinct. Others and we discovered that SARM1 is an essential component of the
injury-activated axonal degeneration program. Importantly, SARM1 is also required for axon loss in models of
neurological disease, including peripheral neuropathies and traumatic brain injury. Hence, agents that block
SARM1 activity are exciting therapeutic candidates for axonal preservation in diseases of axon loss. In the
prior funding period we made a major conceptual breakthrough, discovering that SARM1 is a NAD+ cleaving
enzyme and, hence, a druggable target in the axon degeneration pathway. However, to exploit the full promise
of targeting SARM1 we must understand the molecular mechanisms upstream and downstream of SARM1
enzyme activity. Here we will explore the role of SARM1-derived NAD+ metabolites as biomarkers and
mediators of axon degeneration. We will also identify the mechanisms that keep SARM1 `off' in a healthy axon
and turn SARM1 `on' in a diseased axon. If successful, these studies will define the molecular mechanisms
upstream and downstream of SARM1 enzyme activity and identify novel therapeutic targets for the
preservation of axons in neurological diseases.

## Key facts

- **NIH application ID:** 10198044
- **Project number:** 5R01NS087632-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Aaron Diantonio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $598,620
- **Award type:** 5
- **Project period:** 2014-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198044

## Citation

> US National Institutes of Health, RePORTER application 10198044, Dissection of SARM1-Induced Axon Degeneration and Cell Death (5R01NS087632-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10198044. Licensed CC0.

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