# Stress regulation of neurotransmission

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $412,500

## Abstract

Project Summary
The long-term goal of the proposed research is to identify the mechanisms by which bidirectional
communication between the nervous system and the intestine regulates organism-wide responses to
oxidative stress through regulated neuropeptide release. Oxidative stress plays a critical role in cognitive
dysfunction and neuronal death associated with neurodegenerative diseases, but little is known about the
physiological roles that reactive oxygen species play as signaling molecules in the brain. My laboratory
uses the model C. elegans to study new signaling pathways that modulate neurotransmitter release. We
have identified a role for hydrogen peroxide as a signaling molecule that positively regulates the secretion
of specific neuropeptide-like proteins from dense core vesicles through sulfenylation of dense core vesicle
(DCV) release factors. We found that the regulated release of these neuropeptides activates the
antioxidant transcription factor SKN-1/Nrf2 in the intestine. Here we seek to uncover the molecular
mechanisms by which hydrogen peroxide regulates DCV release, and how, in turn, neuropeptide signaling
activates the antioxidant response. This study will reveal novel mechanisms underlying ROS regulation of
DCV secretion and it will provide fundamental insights into how redox homeostasis is achieved through
gut-brain signaling, and may therefore have direct relevance for the development of strategies to treat
neurodegenerative diseases whose progression is associated with unregulated ROS signaling.

## Key facts

- **NIH application ID:** 10658235
- **Project number:** 2R01NS099414-05A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** DEREK SIEBURTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $412,500
- **Award type:** 2
- **Project period:** 2017-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658235

## Citation

> US National Institutes of Health, RePORTER application 10658235, Stress regulation of neurotransmission (2R01NS099414-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10658235. Licensed CC0.

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