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种(RSS)的氧化还原失衡 心血管疾病，如心肌缺血再灌注(MI/R)损伤和心力衰竭。 硫烷硫化物的应用已被发现会导致心脏保护作用，而硫烷 血浆中硫的生物有效性最近甚至被认为是一种生物标志物 心血管疾病(CVD)。然而，这一领域目前对如何 内源RSS，特别是硫烷硫磺，起作用。我们的长期目标是澄清 在心脏细胞的不同健康阶段的复杂的硫磺途径和利用这一信息 推动心血管疾病早期诊断工具和治疗方法的发展。具体地说，这个项目 将满足拥有有效方法来研究这些途径的迫切需要 化学工具：1)在生物流体存在的情况下，可以定量地“看到细胞/组织” 例如血液和2)只有在亚细胞定位后才开启。这些高度敏感、具体、 可定向/可触发的下一代荧光传感器将使我们能够探测 硫磺对MI/R损伤心肌细胞甚至亚细胞的保护作用 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 预计：1)未来将确定在MI/R动物模型中进行评估的有前途的传感器 2)我们的工具和研究将为提高临床潜力奠定坚实的基础 通过更好地理解硫烷硫磺的作用机理 调节心血管疾病中的氧化还原环境。这一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，获得成功的基本技能 在一家R1机构。一个由赞助商和合作者组成的团队已经与 擅长有机化学和合成、氧化还原生物学、化学生物学、分子和细胞 生物学、计算/数据科学和心血管疾病。进一步的培训将是 从参加会议和演讲中获得教学证书 布朗大学的课程、外展和领导职位。

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.