CAREER: Carbon Monoxide Sensing, Selectivity, and Signaling in Microbes

The supported project studies how microorganisms sense and respond to carbon monoxide (CO) in the environment. CO garners a poor reputation as an imperceptible and lethal gas; however, CO is also a biological signal generated as a metabolic by-product in nearly all organisms on Earth. Such “endogenously produced” CO regulates cellular processes, including cell growth, cell death, and inflammation. CO is also a metabolic intermediate and nutrient for certain microorganisms, serving as a viable source of energy for microbes in nutrient-poor environments. Being a signal and nutrient, CO holds great promise as a potential therapeutic agent and is an underutilized energy currency. However, applications of CO are limited by a poor understanding of how CO is detected in biological systems. This project seeks to identify and characterize biological CO sensors from the microbial world to better establish how CO is detected and how CO detection triggers changes in cellular function. A complementary goal of the project is to improve scientific communication and research skills amongst STEM students while engaging the public through an integrated outreach program related to the biochemistry of blood. This project aims to uncover the molecular principles that govern CO-mediated signal transduction through the study of microbial transcription factors that regulate oxidative CO metabolism. Despite a growing appreciation for the roles of CO as a biological signal and microbial nutrient, a limited number of CO-dependent signaling pathways have been fully elucidated. A key limitation remains the identification of CO sensors proteins that trigger a downstream cellular response. Transcriptional regulators of oxidative CO metabolism offer great utility as models of CO signaling. These microbial transcription factors, which rely on strong coordinate covalent bonding between CO and metal ion-containing cofactors, are more easily expressed than their mammalian counterparts and can be readily identified through functional gene cluster analysis. Building on a combination of functional data and comparative genomics, the research team will integrate cell biology, protein biochemistry, and bioinorganic spectroscopy, to (1) establish unifying protein structural features that confer selective CO signal transduction, and (2) identify novel CO-sensing transcription factors. Completion of these research objectives will have broad-reaching impacts ranging from human health, where CO plays disparate roles as a poison and signal, to ecology and agriculture, where CO may act as an important alternative nutrient source. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2540612 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Matthew Dent | Institution: Wayne State University, DETROIT, MI | Award Amount: $749,702 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540612 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540612.html