Probing the cardioprotective effects of sulfane sulfurs with next generation fluorescent sensors

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Project Summary Redox imbalances of reactive sulfur species (RSS) in cardiac cells contribute to cardiovascular diseases such as myocardial ischemia-reperfusion (MI/R) injury and heart failure. Applications of sulfane sulfurs have been found to cause cardioprotective effects, and sulfane sulfur bioavailability in plasma has even been recently suggested to be a biomarker for cardiovascular disease (CVD). However, this field currently lacks clear understandings as to how endogenous RSS, particularly sulfane sulfurs, work. Our long-term goal is to elucidate the complex sulfane sulfur pathways at various health stages of cardiac cells and use this information to drive the development of early diagnostic tools and therapies for CVD. Specifically, this project will meet the critical need of having effective methods to study these pathways by developing chemical tools that: 1) quantifiably ‘see into cells/tissues’ despite the presence of biological fluids such as blood and 2) turn-on only after subcellular localization. These highly sensitive, specific, and targetable/triggerable next generation fluorescent sensors will allow us to probe the cardioprotective roles of sulfane sulfurs in cardiac cell models of MI/R injury even to subcellular extents and non-invasively decipher complex cardiovascular sulfur-mediated redox pathways. We expect that: 1) promising sensors will be identified for future evaluations in animal models of MI/R and 2) our tools and studies will establish a strong basis for advancing the clinical potential of sulfane sulfurs through a greater understanding of the mechanisms by which sulfane sulfurs regulate redox environments in CVD. The long-term goal for this fellowship award is to develop essential skills for a successful career as a chemical biology professor studying human diseases at an R1 institution. A team consisting of the sponsor and collaborators has been assembled with expertise in organic chemistry and synthesis, redox biology, chemical biology, molecular and cell biology, computational/data sciences, and cardiovascular diseases. Further training will be obtained from conference attendance and presentations in conjunction with teaching certificate programs, outreach, and leadership positions at Brown University.