The long-term goal of this research is to develop and apply purpose-inspired chemical tools for detecting, quantifying, and delivering biological hydrogen sulfide (H2S). Hydrogen sulfide is now accepted as an important physiological mediator and signaling agent, joining NO and CO as an endogenous gasotransmitter. H2S plays important roles in various conditions associated with human health including diabetes, hypertension, atherosclerosis, inflammation, neurodegeneration, sepsis, and asthma. Upon enzymatic production, H2S exerts its action on different molecular targets, including ion channels and signaling proteins through reaction with protein thiols and transition-metal centers. Despite the diverse and important biochemical roles of H2S, limited methods are available for detecting, quantifying, or delivering biologically-relevant H2S concentrations. Although many of the reported chemical tools for H2S work well in non-biological settings, few of these tools have proven sufficiently sharp to make the transition from test tubes to real biological contexts. To address these unmet needs, the objectives in this proposal are to develop and refine purpose-inspired chemical tools for biological H2S detection, quantification, and delivery and to apply these tools to investigate host-microbial interactions in live zebrafish. The rational for this wor is that successful completion of the proposed Aims will provide robust chemical tools and provide a positive impact toward studying and understanding the multifaceted roles of H2S in biology. Motivated by proof-of-concept preliminary results supporting the research design, specific aims include: 1) Development and application of selective reporters for H2S; 2) Development and application of traceable, slow-release H2S donors; 3) Functional imaging of H2S and microbial colonization dynamics in zebrafish. Objectives outlined in the first Aim include new platforms to translate H2S imaging into biologically-relevant concentration ranges by using bright pH insensitive chromophores, targeted H2S sensors, and signal amplification methods to lower the detection limits of H2S probes. Objectives outlined in the second Aim include new innovative strategies for coupling H2S delivery with an optical readout to facilitate non- invasive, real-time monitoring of H2S delivery to bridge the gap between cuvette- and context-based measurements of H2S release. Objectives outlined in the third Aim include imaging H2S production in conventional, germ-free, and monobacterial zebrafish, and determining the role of H2S on microbial gut colonization dynamics. The proposed research is significant because the outlined approaches directly address current unmet needs and limitations in the field related to H2S imaging, quantification, and delivery. Successful completion of the proposed Aims will provide a positive impact in the field of H2S biochemistry and will result a greater understanding of the important and multifaceted roles of H2S associated with human health.

Public Health Relevance

The proposed research involves the design of chemical tools for detecting, quantifying, and delivering biological hydrogen sulfide and their application in investigating the role of H2S in zebrafish gut microbiota. This research is relevant to public health because hydrogen sulfide is an important physiological mediator with documented roles diabetes, hypertension, atherosclerosis, inflammation, neurodegeneration, sepsis, and asthma. Because these developed chemical tools will facilitate a greater understanding the multifaceted roles of H2S in biological contexts, the proposed research is relevant to the NIH's mission that pertains to developing and expanding fundamental knowledge to help reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM113030-01A1
Application #
8965404
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Oregon
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Eugene
State
OR
Country
United States
Zip Code
97403
Steiger, Andrea K; Zhao, Yu; Pluth, Michael D (2018) Emerging Roles of Carbonyl Sulfide in Chemical Biology: Sulfide Transporter or Gasotransmitter? Antioxid Redox Signal 28:1516-1532
Zhao, Yu; Steiger, Andrea K; Pluth, Michael D (2018) Cysteine-activated hydrogen sulfide (H2S) delivery through caged carbonyl sulfide (COS) donor motifs. Chem Commun (Camb) 54:4951-4954
White, Brittany M; Zhao, Yu; Kawashima, Taryn E et al. (2018) Expanding the Chemical Space of Biocompatible Fluorophores: Nanohoops in Cells. ACS Cent Sci 4:1173-1178
Steiger, Andrea K; Zhao, Yu; Choi, Won Jin et al. (2018) Investigations into the carbonic anhydrase inhibition of COS-releasing donor core motifs. Biochem Pharmacol 149:124-130
Steiger, Andrea K; Marcatti, Michela; Szabo, Csaba et al. (2017) Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H2S Donors. ACS Chem Biol 12:2117-2123
Cerda, Matthew M; Hammers, Matthew D; Earp, Mary S et al. (2017) Applications of Synthetic Organic Tetrasulfides as H2S Donors. Org Lett 19:2314-2317
Zhao, Yu; Henthorn, Hillary A; Pluth, Michael D (2017) Kinetic Insights into Hydrogen Sulfide Delivery from Caged-Carbonyl Sulfide Isomeric Donor Platforms. J Am Chem Soc 139:16365-16376
Steiger, Andrea K; Pardue, Sibile; Kevil, Christopher G et al. (2016) Self-Immolative Thiocarbamates Provide Access to Triggered H2S Donors and Analyte Replacement Fluorescent Probes. J Am Chem Soc 138:7256-9
Montoya, Leticia A; Pluth, Michael D (2016) Organelle-Targeted H2S Probes Enable Visualization of the Subcellular Distribution of H2S Donors. Anal Chem 88:5769-74
Zhao, Yu; Pluth, Michael D (2016) Hydrogen Sulfide Donors Activated by Reactive Oxygen Species. Angew Chem Int Ed Engl 55:14638-14642

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