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Reactive oxygen species (ROS) are highly reactive molecules and free radicals derived from molecular oxygen. ROS are a natural byproduct of oxygen usage. Examples include superoxide, hydrogen peroxide, and hydroxyl radicals:



ROS perform dual roles in cells, acting as both destructive and constructive agents. At high levels, ROS mediate irreversible cellular damage and are associated with a wide range of disease pathologies including diabetes, neurodegeneration, and cancer. Many therapeutic efforts center on the prevention and treatment of oxidative stress-related disease with antioxidant therapeutics aimed to counteract ROS. At lower physiological levels, ROS play important roles in the activation of beneficial signaling events. Completely depleting ROS will limit the bioavailability of ROS for beneficial signaling.

Despite the emerging appreciation for ROS as constructive signaling agents, relatively few redox-signaling pathways mediated by ROS have been characterized. Our research program focuses on broadening our knowledge of ROS-based signaling events. Our overarching goal is to elucidate individual signaling 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. Understanding how ROS facilitates signaling will ultimately enable better therapeutics that both limit ROS-induced damage and maintain beneficial cell signaling pathways.




A major and ongoing focus of the lab is the elucidation of pathways that sense and respond to ROS generated at the endoplasmic reticulum (ER). ROS (H2O2) are produced as a byproduct of disulfide bond formation in the ER, yet we as a field are just beginning to uncover the systems that prevent oxidant accumulation and damage as a consequence of oxidative folding.


Our lab 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? What are the physiological outcomes for BiP oxidation and/or for a dysruption in  BiP oxidation or reduction?




A second focus in the lab is understanding the role of methionine oxidation (MetO formation) and resolution in cells. We are focused on what we consider the most prominent gaps in our knowledge of MetO: What are the physiological targets and outcomes of MetO formation? What is the role for methionine sulfoxide reductases (MsrA and MsrB) 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.

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