# Stress Regulation of Synaptic Transmission

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $360,938

## Abstract

Principal Investigator: Derek Sieburth
Project Summary
The long-term goal of the proposed research is to identify the mechanisms through which bidirectional
communication between the nervous system and distal tissues regulates organism-wide responses to
oxidative stress. Oxidative stress plays a critical role in cognitive dysfunction and neuronal death
associated with neurodegenerative diseases. Nrf2 is a transcription factor that plays a key role in cellular
resistance to oxidative stress, but little is known about the physiological signals that regulate Nrf2 activity
in the brain or how Nrf2 impacts neuronal function. My laboratory uses the model C. elegans to study new
signaling pathways that modulate presynaptic function. We recently identified the Nrf2 homolog, SKN-1,
as a regulator of presynaptic structure and function. We found that SKN-1/Nrf2 functions cell non-
autonomously to regulate neurotransmitter secretion from neuromuscular junctions. We also found that
neuroendocrine signaling from the nervous system confers organism-wide protection from the toxic effects
of oxidative stress by activating SKN-1/Nrf2 in distal tissues. Here we seek to uncover the cellular and
molecular mechanisms by which bidirectional communication between the nervous system and distal
tissues promotes an adaptive response to oxidative stress through the regulation of neurotransmitter
secretion. In Aim 1, we will determine how SKN-1/Nrf2 activity is positively regulated by neuropeptide
release from the nervous system. In Aim 2, we will determine how reactive oxygen species promote
neuropeptide release in vivo. In Aim 3 we will determine how synaptic transmission is negatively regulated
by cell non-autonomous SKN-1 activation. Nrf2 activation protects neurons form death in a variety of
neurodegenerative disease models, and our research may uncover new endogenous activators of Nrf2,
which may lead to the development of new therapeutics that can prevent or treat these diseases.

## Key facts

- **NIH application ID:** 9882353
- **Project number:** 5R01NS099414-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** DEREK SIEBURTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,938
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882353

## Citation

> US National Institutes of Health, RePORTER application 9882353, Stress Regulation of Synaptic Transmission (5R01NS099414-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9882353. Licensed CC0.

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