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

项目摘要 心肌细胞中活性硫物质（RSS）的氧化还原失衡有助于 心血管疾病，如心肌缺血-再灌注（MI/R）损伤和心力衰竭。 已发现硫烷硫的应用可引起心脏保护作用， 血浆中硫的生物利用度最近甚至被认为是 心血管疾病（CVD）。然而，这一领域目前缺乏明确的认识， 内源性RSS，特别是硫烷硫，起作用。我们的长期目标是阐明 复杂的硫烷硫途径在不同的健康阶段的心脏细胞，并使用这些信息 推动CVD早期诊断工具和治疗方法的发展。具体来说，这个项目 将通过开发有效的方法来研究这些途径， 化学工具：1）尽管存在生物液体，但可以定量地“看到细胞/组织” 如血液，和2）仅在亚细胞定位后开启。这些高度敏感、特异、 和可靶向/可植入的下一代荧光传感器将使我们能够探测 硫烷硫在心肌梗死/再灌注损伤模型中的心脏保护作用， 范围和非侵入性破译复杂的心血管硫介导的氧化还原途径。我们 我希望：1）有前途的传感器将被确定为未来在MI/R动物模型中的评价 2）我们的工具和研究将为推进临床潜力奠定坚实的基础。 通过更好地了解硫烷硫的机制来了解硫烷硫 调节CVD中的氧化还原环境。该奖学金的长期目标是发展 作为一名研究人类疾病的化学生物学教授， 在R1机构。一个由赞助商和合作者组成的团队已经组建， 在有机化学和合成、氧化还原生物学、化学生物学、分子和细胞方面的专业知识 生物学、计算/数据科学和心血管疾病。进一步培训将 从会议出席和演讲中获得，并获得教学证书 计划，推广，并在布朗大学的领导地位。

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.