Chemical Tools for Understanding the Redox Biology of Reactive Sulfur Species

项目摘要 反应性硫物质，如过硫化物（RSSH）和多硫化氢（H2Sn）， 在氧化还原生物学中的调节作用。调节它们的细胞水平可能具有潜在的治疗作用。 值然而，其确切的作用机制仍不清楚。一些基本 关于这些物种的化学性质的问题必须得到解决，然后我们才能期待一个 生物学理解或临床应用。了解这些物种的反应性至关重要 并认识到在生物测量中测量它们时可能产生的限制和误差， 样品在这方面，研究工具，准确和方便地检测这些硫物种 是迫切需要的。我们的实验室最近发现了RSSH的一些独特的化学和反应 和H2Sn。基于这些发现，我们预计，高度敏感和具体的化学工具， 可以开展RSSH和H_2Sn的研究。我们还希望这些工具能够使我们更好地 了解RSSH和H2Sn的生物学意义。在这个应用程序中，我们计划追求三个 具体目标：1）开发新的RSSH生成方法和定量标记策略， 蛋白质组学特征的蛋白质S-巯基化，2）建立新的化学和成像 多硫化氢的探针; 3）评估活性硫物质对 蛋白S-硫水合作用及其对应激调节的影响。这项研究将使我们 为了建立用于产生特定类型的活性硫物质的新试剂和方案， 用于成像这些物种的探针，以及优化的定量蛋白质组学方法， 分析受活性硫物质影响的蛋白质翻译后修饰。

PROJECT SUMMARY Reactive sulfur species such as persulfides (RSSH) and hydrogen polysulfides (H2Sn) play regulatory roles in redox biology. Modulation of their cellular levels could have potential therapeutic value. However, their exact mechanisms of action are still unclear. A number of fundamental questions concerning the chemistry of these species must be addressed before we can expect a biological understanding or clinical applications. It is vital to understand the reactivity of these species and to appreciate the limitation and errors that may be generated when measuring them in biological samples. In this context, research tools for accurate and convenient detection of these sulfur species are urgently needed. Our lab has recently discovered some unique chemistry and reactions of RSSH and H2Sn. Based on these discoveries, we expect that highly sensitive and specific chemical tools for the study of RSSH and H2Sn can be developed. We also expect these tools will enable us to better understand the biological significance of RSSH and H2Sn. In this application, we plan to pursue three specific aims: 1) to develop new RSSH generation methods and labeling strategies for quantitative proteomics characterization of protein S-sulfhydration, 2) to establish new chemistry and imaging probes for hydrogen polysulfides; 3) to assess the distinctive contribution of reactive sulfur species on protein S-sulfhydration and its implications on stress regulation. The proposed research will allow us to establish novel reagents and protocols for generating specific types of reactive sulfur species, new probes for imaging such species, and optimized quantitative proteomics approaches for effective profiling of protein posttranslational modifications impacted by reactive sulfur species.