# Developing Novel Neuroprotective Strategies for EAE/Optic Neuritis

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $469,519

## Abstract

PROJECT SUMMARY
Optic neuritis is one of the most common clinical manifestations of Multiple Sclerosis (MS). It causes severe
visual loss due to inflammatory demyelination of the optic nerve (ON) and subsequent degeneration of ON and
retinal ganglion cells (RGCs). The significant unmet clinical need for neuroprotectants is due to the lack of
understanding of the key upstream signals that trigger the neurodegenerative cascade. Our previous studies
demonstrated that both acute and chronic ON injury induce endoplasmic reticulum (ER) stress in RGCs. We
were able to protect the injured RGC soma and axons if we blocked the detrimental effects of ER stress by
manipulating two key downstream molecules of the unfolded protein response (UPR) in opposite ways: a)
deletion of CCAAT/enhancer binding protein homologous protein (CHOP), and/or b) activation of X-box binding
protein 1 (XBP-1). Thus axon injury-induced ER stress may be a common mechanism of neuronal damage and
targeting neuronal ER stress may have considerable therapeutic neuroprotective potential in diseases
associated with axonopathy. The rodent experimental autoimmune encephalomyelitis (EAE) model induced by
immunization with myelin proteins replicates many clinical symptoms and pathological signs of MS, including
optic neuritis and significant RGC soma and axon loss. ER stress has been detected in white and grey matter
of MS patients' brains and in EAE mice. We confirmed the role of neuronal ER stress in autoimmune-induced
neurodegeneration in EAE. Furthermore, exciting recent studies of axonal Wallerian degeneration have shown
that several key molecules involved in axonal NAD+ metabolism are critical for axonal degeneration. SARM1
(Sterile Alpha and TIR Motif 1), for example, is negatively regulated by axonal NAD+ synthetic enzyme
nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) to induce axon degeneration; deletion of
SARM1 or activation of axonal NMNATs results in axon protection. Here we propose to test the hypothesis that
modulating both intrinsic neuronal ER stress and NAD+ metabolism will synergistically prevent both
RGC soma and axon (ON) degeneration and preserve vision in EAE/optic neuritis. We anticipate that this
study will unambiguously identify novel therapeutic targets and that our findings will ultimately be translated
safely into innovative neuroprotective treatments for patients with MS and optic neuritis.

## Key facts

- **NIH application ID:** 9963222
- **Project number:** 5R01EY028106-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Yang Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,519
- **Award type:** 5
- **Project period:** 2018-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963222

## Citation

> US National Institutes of Health, RePORTER application 9963222, Developing Novel Neuroprotective Strategies for EAE/Optic Neuritis (5R01EY028106-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963222. Licensed CC0.

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