Reactive sulfur, oxygen, and nitrogen (RSON) species are endogenous small molecules that play fundamental roles in cellular signaling and are misregulated in diseases ranging from cancer to neurodegeneration to diabetes. This super-family of signaling molecules includes nitric oxide, hydrogen sulfide, hydrogen peroxide, and many others. Despite being involved in nearly all physiological processes, our understanding of their complex and intertwined roles remains in its infancy due, in large part, to a lack of methods to monitor these transient species in living cells and human clinical samples. This project aims to use highly innovative chemistry to develop responsive fluorescent dyes for the precise real-time tracking of specific RSON species, including hydrogen sulfide, peroxynitrite, and nitroxyl, and to use these probes to investigate their production in cellular models of lung cancer and in human saliva/exhaled breath condensates. Specifically, we aim to: 1. Develop reaction-based probes to detect and image RSON species in cells and clinical samples. There is a lack of biologically compatible methods for the detection of certain RSON species, particularly hydrogen sulfide, peroxynitrite, and nitroxyl. Leveraging our expertise in synthetic organic chemistry, we will bridge this gap by inventing new reaction-based probes to detect and image these species using fluorescence, chemiluminescence, and nuclear magnetic resonance techniques. 2. Investigate the role of RSON species in cellular models of disease. Although the ubiquitous signaling molecule nitric oxide has been well studied in cancer models, the production and roles of other RSON species remain incompletely understood. We will use newly developed and state-of-the-art reaction-based probes to characterize the complex cellular chemistry of RSON species in a cellular model of airway inflammation. 3. Develop and validate point-of-care diagnostics for the detection and management of disease. RSON chemistry has the potential to be a powerful diagnostic and prognostic marker. Indeed, exhaled nitric oxide and H2O2 are established biomarker for monitoring asthma and other respiratory ailments, but home and point-of-care monitoring remains a significant obstacle. We will develop innovative point-of-care smartphone-based RSON detection techniques for monitoring the levels of these species in the saliva and exhaled breath condensates.

Public Health Relevance

Our project focuses on developing innovative tools to help understand how endogenous reactive sulfur, oxygen, and nitrogen (RSON) species impact human health and disease. By designing highly creative molecular scaffolds, we can translate these reactive and transient species into an observable optical or magnetic resonance signal, enabling real-time visualization in living cells and precise measurement in clinical samples. Using these tools to unravel how misregulation of the complex biological chemistry of RSON species contributes to disease will increase our understanding at a fundamental level. Innovative optical methods will enable smartphone detection of these species at the point-of-care, providing powerful tools for disease monitoring. These newly developed methods will be made available to researchers worldwide, generating a significant impact on human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
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Southern Methodist University
Schools of Arts and Sciences
United States
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Cao, Jian; An, Weiwei; Reeves, Audrey G et al. (2018) A chemiluminescent probe for cellular peroxynitrite using a self-immolative oxidative decarbonylation reaction. Chem Sci 9:2552-2558
Reeves, A G; Subbarao, M; Lippert, A R (2017) Imaging Acetaldehyde Formation During Ethanol Metabolism in Living Cells using a Hydrazinyl Naphthalimide Fluorescent Probe. Anal Methods 9:3418-3421
Quimbar, Miguel E; Krenek, Katherine M; Lippert, Alexander R (2016) A chemiluminescent platform for smartphone monitoring of H2O2 in human exhaled breath condensates. Methods 109:123-130
Cao, Jian; Campbell, James; Liu, Li et al. (2016) In Vivo Chemiluminescent Imaging Agents for Nitroreductase and Tissue Oxygenation. Anal Chem 88:4995-5002