The candidate received his Ph.D. from the UC Berkeley, under the joint direction of Kenneth Raymond and Robert Bergman where he studied host-guest chemistry, molecular recognition, and catalysis in water-soluble supramolecular complexes. He is currently an NIH postdoctoral fellow in Stephen Lippard's laboratory at MIT working on developing fluorescent probes for nitric oxide. The candidate's research interests span the field of molecular recognition with a specific focus on how microscopic processes lead to the recognition of individual atoms, functional groups and molecules. The candidate will use his background in mechanistic studies and molecular recognition to pursue his research interests as a principle investigator. His independent research will focus on the development of new tools for the detection and imaging of small molecules in biology. Nitric oxide (NO) and hydrogen sulfide (H2S) are now accepted as biologically important gaseous transmitters. Both NO and H2S are produced endogenously and are finely regulated by the body. Nitric oxide is beneficial for vasodilation and immune activity at low cellular concentrations but overproduction can lead to the proliferation of reactive NO species that have been implicated in carcinogenesis and several degenerative neurological disorders, including Alzheimer's (AD), Parkinson's, and Huntington's disease, as well as multiple sclerosis. Similarly, H2S has been implicated in AD, Downs syndrome and other forms of metal deficiency. H2S also plays an active role in inflammation and in blood pressure regulation. Despite the recognized importance of both of these gaseous transmitters, the current methods for detection in live cells are limited. The postdoctoral phase of the proposed research will focus on the development of new NO-selective fluorescent probes that address current limitations of NO detection. Transition metal based NO binding sites will be used to develop probes that can reversibly bind NO and probes that emit in the NIR. The proposed family of fluorescent probes will use paramagnetic (S=1/2) metals serving the dual role as both fluorescence quencher and NO binding site. Coordination of NO will form a diamagnetic (S=0) complex and restore the fluorescence of the pendant fluorophore. Adsorption or covalent attachment of such complexes to solubilized single-walled carbon nanotubes (SWNTs) will be used to develop NO-selective probes that emit in the NIR. The independent research phase of the proposed research will investigate the design of H2S-selective fluorescent probes for the imaging of endogenously produced H2S. Currently, such H2S detection methods are lacking and most measurements rely on bulk tissue measurements. The new H2S-selective fluorescent probes for use in live cells will provide much needed tools for the study of the biological functions of H2S. The unique physical properties of H2S will all be exploited in the design of H2S-selective fluorescent probes. Fluorophores will be derivatized with specially designed protecting groups that can only be removed by H2S. Removal of the fluorophore protecting group will restore the fluorescence, thus forming a turn-on probe for H2S.

Public Health Relevance

Both nitric oxide (NO) and hydrogen sulfide (H2S) have been identified as important endogenous gaseous transmitters in the human body and have been implicated in carcinogenesis, hypertension, and several neurological disorders including Alzheimer's disease, Parkinson's disease, Downs syndrome, and multiple sclerosis. Despite this interest, there are currently few methods to detect or image intracellular levels of these small molecule transmitters. This proposal presents the design of fluorescent probes for NO and H2S, which would allow for the selective detection and imaging of these endogenous gasses in live cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Fabian, Miles
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University of Oregon
Schools of Arts and Sciences
United States
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Spencer Bailey, T; Pluth, Michael D (2015) Chemiluminescent detection of enzymatically produced H2S. Methods Enzymol 554:81-99
Hammers, Matthew D; Taormina, Michael J; Cerda, Matthew M et al. (2015) A Bright Fluorescent Probe for H2S Enables Analyte-Responsive, 3D Imaging in Live Zebrafish Using Light Sheet Fluorescence Microscopy. J Am Chem Soc 137:10216-23
Sonke, Eric; Verrydt, Megan; Postenka, Carl O et al. (2015) Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential. Nitric Oxide 49:26-39
McGrath, Jacqueline M; Pluth, Michael D (2014) Understanding the effects of preorganization, rigidity, and steric interactions in synthetic barbiturate receptors. J Org Chem 79:711-9
Hammers, Matthew D; Pluth, Michael D (2014) Ratiometric measurement of hydrogen sulfide and cysteine/homocysteine ratios using a dual-fluorophore fragmentation strategy. Anal Chem 86:7135-40
Montoya, Leticia A; Pluth, Michael D (2014) Hydrogen sulfide deactivates common nitrobenzofurazan-based fluorescent thiol labeling reagents. Anal Chem 86:6032-9
Bailey, T Spencer; Zakharov, Lev N; Pluth, Michael D (2014) Understanding hydrogen sulfide storage: probing conditions for sulfide release from hydrodisulfides. J Am Chem Soc 136:10573-6
Hartle, Matthew D; Sommer, Samantha K; Dietrich, Stephen R et al. (2014) Chemically reversible reactions of hydrogen sulfide with metal phthalocyanines. Inorg Chem 53:7800-2
Montoya, Leticia A; Pearce, Taylor F; Hansen, Ryan J et al. (2013) Development of selective colorimetric probes for hydrogen sulfide based on nucleophilic aromatic substitution. J Org Chem 78:6550-7
Bailey, T Spencer; Pluth, Michael D (2013) Chemiluminescent detection of enzymatically produced hydrogen sulfide: substrate hydrogen bonding influences selectivity for H2S over biological thiols. J Am Chem Soc 135:16697-704

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