# Molecular mechanisms of cellular redox signaling

> **NIH NIH R35** · CORNELL UNIVERSITY · 2024 · $70,646

## Abstract

Abstract
Reactive oxygen species (ROS) perform dual roles in cells, acting as both destructive and constructive agents.
At high levels, intracellular ROS facilitate irreversible macromolecular damage and are associated with a range
of disease pathologies. At lower physiological levels, ROS play important roles in the activation of beneficial
signaling events through the reversible post-translational modification of cysteine and methionine residues.
Despite the emerging appreciation for ROS as constructive signaling agents, and the importance for functional
redox signaling in managing cellular ROS, relatively few redox-signaling pathways have been characterized.
Many proteins susceptible to oxidation have been cataloged. However, the consequences of oxidation and the
physiological outcomes have been established for only a limited number of these targets. We argue this central
knowledge gap limits larger efforts towards the development of effective therapeutics to help manage cellular
ROS. Since its inception, our research program has focused on broadening our knowledge of ROS-based
signaling events. Our overarching goal is to elucidate individual pathways activated by the modification of
protein cysteine and/or methionine by ROS. Our intent is to uncover and to characterize redox-signaling
components, including ROS sources, redox targets, and oxidation regulators, as well as the consequences
(outcomes) for signaling at the protein and physiological level. Our research efforts center on two focus areas:
(1) an analysis of the role for cysteine oxidation in managing ROS within the endoplasmic reticulum (ER) and
(2) the study of the consequences of protein methionine oxidation (MetO) formation and reduction. Our prior
work established that oxidation of a conserved cysteine in the Hsp70 BiP alters its chaperone activity to sustain
ER function under elevated ROS conditions. Our ongoing work intends to broaden our understanding of redox
signaling at the ER and BiP oxidation, answering the questions: What are the local endogenous sources of
ROS in the ER that are sensed by BiP? How does BiP oxidation influence known ER stress response
pathways? In addition, we intend to bolster the fundamental understanding of MetO formation and resolution
in cells, focusing in parallel on what we consider the most prominent gaps in our knowledge of MetO: What are
the physiological targets of MetO? What is the role for methionine sulfoxide reductases in regulating individual
protein MetO events throughout the cell? By answering these questions, we intend to provide insight into the
basic cell functions used to manage cellular ROS and avert cellular damage. We anticipate that our experience
and expertise, coupled with a diversity of personnel and scientific approaches, will allow us to make sustained
research progress over this MIRA award.

## Key facts

- **NIH application ID:** 11100657
- **Project number:** 3R35GM152166-01S1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Carolyn S Sevier
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $70,646
- **Award type:** 3
- **Project period:** 2024-01-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100657

## Citation

> US National Institutes of Health, RePORTER application 11100657, Molecular mechanisms of cellular redox signaling (3R35GM152166-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11100657. Licensed CC0.

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