A Comparative Approach to Understanding the Physical Effects and Processing of Hydrogen Sulfide: Pharmacological Manipulations and Gene Regulatory Mechanisms
Abstract
Hydrogen sulfide (H2S) is a gas that has long been studied for its toxic properties, as it interferes with energy metabolism. The general paradigm of H2S biology has been that organisms should minimize endogenous sulfide concentrations and have adaptations to limit its adverse effects. Recent research, however, indicates that H2S has a variety of molecular targets, affects multiple biological processes, and plays a role as a cellular signaling molecule. This has fueled research towards application of H2S as a therapeutic and refocused interest in mechanisms underlying H2S homeostasis, including detoxification and production routes. Despite the prospect for biomedical applications, major questions remain about H2S metabolism, its regulation, and how physiological effects documented in vitro apply to whole organismal functioning. With a previous grant, we have established a unique fish model that includes populations susceptible to H2S and derived, H2S-tolerant populations living in springs with H2S concentrations orders of magnitude higher than what most metazoans can cope with. This natural variation in H2S tolerance provides unique opportunities to address questions about molecular mechanisms underlying responses to H2S. Our work has shown that responses to H2S both across evolutionary timescales (population differences) and across physiological timescales (individual responses upon exposure) involve complex changes in gene regulation. Building on this work, we combine experimental approaches with cutting-edge genomic analyses to address the following questions: (1) What gene expression changes are a direct consequence of H2S? Most studies assume that measured physiological effects of H2S manipulations are directly caused by H2S interfering with specific molecular targets. However, documented physiological effects may indirectly arise when H2S-mediated disruptions of cellular homeostasis cascade through interconnected physiological systems. We will combine environmental H2S exposures with pharmacological tools that allow for targeted H2S-release in the cytosol and mitochondria to measure organismal H2S responses. (2) What are the regulatory mechanisms mediating expression variation in key genes involved in maintaining H2S homeostasis? The physiological pathways involved in H2S processing have been well-characterized, and responses to H2S both at evolutionary and physiological timescale involve differential expression of components of these pathways. However, it remains largely unknown what mechanisms mediate the documented gene expression changes. We will leverage heritable, among-population variation in the expression of key genes and utilize a quantitative genetics approach to identifying genomic regions influencing expression levels of mRNA. This will represent a first critical step to identify cis and trans regulatory elements underlying responses to H2S. Overall, this project represents a critical in vivo test of the relevance of H2SÕs hypothesized physiological effects documented in vitro, and the comparison of H2S-tolerant and non-tolerant populations is expected to reveal mechanisms underlying the maintenance H2S homeostasis. The proposed study combines experimental approaches in the laboratory with integrative analyses of genomic datasets. It will significantly contribute to a basic understanding of the physiological effects and processing of H2S. Basic knowledge of organismal H2S processing will be requisite its safe applications as a proposed therapeutic. This is of great value for the U.S. military, because H2S can protect organisms from lethal blood loss and has the potential to profoundly affect practices in combat casualty care and the treatment of traumatic injuries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 09, 2020
- Source ID
- W911NF2010124
Entities
People
- Michael Tobler
Organizations
- Army Contracting Command
- Kansas State University
- United States Army