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

使用下一代荧光传感器探讨硫烷硫的心脏保护作用

• 批准号: 10749202
• 负责人: Meg Shieh
• 金额: $ 4.77万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749202
• 关键词: Address; Advanced Development; Animal Model; Autophagocytosis; Award; Biological; Biological Assay; Biological Availability; Biological Markers; Biological Models; Biological Phenomena; Biology; Blood; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell model; Cells; Cellular biology; Chemicals; Clinical; Complex; Confocal Microscopy; Data; Data Science; Detection; Development; Diagnostic; Disease; Educational process of instructing; Environment; Evaluation; Exhibits; Exposure to; Fellowship; Flow Cytometry; Fluorescence; Fluorescence Microscopy; Fluorescent Dyes; Future; Goals; Health; Heart Diseases; Heart failure; Homeostasis; Hydrogen Sulfide; In Vitro; Individual; Institution; Knowledge; Lasers; Leadership; Liquid substance; Machine Learning; Maps; Mediating; Methods; Modification; Molecular Biology; Myocardial Ischemia; Myocardial Reperfusion Injury; Organelles; Organic Chemistry; Organic Synthesis; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Plasma; Positioning Attribute; Procedures; Protocols documentation; Recording of previous events; Reperfusion Therapy; Role; Signaling Molecule; Sincalide; Specificity; Sulfur; System; Testing; Therapeutic; Tissues; Training; Tube; Universities; Work; biological systems; cardioprotection; cardiovascular disorder therapy; career; certificate program; combat; commercialization; cytotoxicity; design; detection method; diagnostic tool; ethnic disparity; fluorophore; gender disparity; human disease; improved; near infrared dye; next generation; novel; outreach; oxidative damage; prevent; professor; quantum; ratiometric; response; sensor; skills; symposium; therapeutic target; thioester; tool

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.

项目摘要 心脏细胞中反应性硫种（RSS）的氧化还原不平衡有助于 心血管疾病，例如心肌缺血 - 再灌注（MI/R）损伤和心力衰竭。 已经发现硫烷硫的应用会引起心脏保护作用，硫 血浆中的硫生物利用度甚至最近被认为是 心血管疾病（CVD）。但是，该领域目前对如何了解 内源性RS，尤其是硫硫硫的作用。我们的长期目标是阐明 在心脏细胞的各个健康阶段，复杂的硫烷硫途径，并使用此信息 推动开发CVD的早期诊断工具和疗法。具体来说，这个项目 将满足具有有效方法来研究这些途径的关键需求 化学工具：1）Quantifcional“看到细胞/组织”进行生物流体的存在 例如血液和2）仅在亚细胞定位后转旋。这些高度敏感，具体， 并且可靶向/可触发的下一代荧光传感器将使我们能够探测 硫烷硫硫硫在MI/R损伤的心脏细胞模型中的心脏保护作用，即 范围和非侵入性破译复合物心血管硫介导的氧化还原途径。我们 预期：1）将确定有希望的传感器以在MI/R的动物模型中进行未来评估 2）我们的工具和研究将为促进临床潜力建立强大的基础 通过对硫烷硫的机制有更深入的了解 调节CVD中的氧化还原环境。该奖学金奖的长期目标是发展 作为研究人类疾病的化学生物学教授，成功职业生涯的基本技能 在R1机构。由赞助商和合作者组成的团队已与 有机化学与合成，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。进一步的培训将是 与教学证书一起从会议出勤和演讲中获得 布朗大学的计划，外展和领导职务。