Generation and Reactivity of Reactive Sulfur Species

活性硫物质的生成和反应性

• 批准号: 2247616
• 负责人: John Toscano
• 金额: $ 57.5万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2247616&HistoricalAwards=false
• 关键词: Generation; Reactivity; Reactive; Sulfur; Species

With this award, the Chemical Structure, Dynamics & Mechanisms-B Program continues its support of the work of Professor John P. Toscano of the Chemistry Department at Johns Hopkins University. The research will involve the generation and reactivity of biologically relevant reactive sulfur species, including hydropersulfides (RSSH). Hydrogen sulfide (H2S) is an endogenously generated small molecule signaling agent whose diverse physiological effects have been well documented. The chemical mechanisms responsible for these effects, however, remain inadequately defined. Recent reports indicate that much of H2S biological activity may be attributed to RSSH, which have been reported to be involved in the modification of protein cysteine residues (PSH) to generate protein hydropersulfides (PSSH). Recently, there has been intense interest in the physiological functions of these species. For example, protein persulfidation has been shown to be dysregulated and reduced in neurological disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. The research will afford broad, comprehensive training for graduate students and undergraduates, serving them well for future opportunities in both industry and academia. Undergraduate participation in research will continue to be a high priority since previous students have indicated that this experience was the highlight of their college careers and was instrumental in clarifying their interests and preparing them for future studies. An integrated, after school science outreach experience for high school students focusing on the chemistry/biology interface will also be developed.Despite increasing evidence for the role of RSSH in physiological redox signaling, the biologically relevant chemistry of RSSH is still relatively poorly understood. One way to predict the biological functions of RSSH is to understand their fundamental chemistry. Thus, one focus of the proposed research is further exploration of the fundamental chemical properties of RSSH and related reactive sulfur species. Because RSSH are unstable and decomposes rapidly into a variety of species, they are inherently difficult to study in aqueous solution and are typically generated in situ. Although several strategies for RSSH generation have been reported, there is still an unmet need for the further development of new methods for the efficient and controlled production of RSSH for biological applications. Thus, the development of novel RSSH photoprecursors and protein persulfidating reagents, designed to react cleanly with small molecule thiols to produce RSSH and protein cysteine residues to produce PSSH, will also be evaluated.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

通过这一奖项，化学结构、动力学和机制-B项目继续支持约翰·霍普金斯大学化学系约翰·P·托斯卡诺教授的工作。这项研究将涉及生物上相关的活性硫物种的生成和反应性，包括过硫化物(RSSH)。硫化氢(H_2S)是一种内源性小分子信号转导物质，其多种生理效应已有文献记载。然而，造成这些影响的化学机制仍然没有得到充分的界定。最近的报道表明，H_2S的大部分生物活性可能归因于RSSH，据报道，RSSH参与了蛋白质半胱氨酸残基(PSH)的修饰以生成蛋白质过硫化物(PSSH)。最近，人们对这些物种的生理功能产生了浓厚的兴趣。例如，在阿尔茨海默氏症、帕金森氏症和亨廷顿病等神经系统疾病中，蛋白质过硫化被证明是不受调控的，并且减少了。这项研究将为研究生和本科生提供广泛、全面的培训，为他们未来在行业和学术界的机会提供良好的服务。本科生参与研究将继续是一个高度优先的问题，因为以前的学生已经表示，这段经历是他们大学生涯中的亮点，有助于澄清他们的兴趣，帮助他们为未来的学习做好准备。还将为高中生开发一种综合的课外科学推广体验，重点放在化学/生物界面上。尽管越来越多的证据表明RSSH在生理氧化还原信号中的作用，但RSSH的生物学相关化学仍然相对较少。预测RSSH生物学功能的一种方法是了解它们的基础化学。因此，建议的研究重点之一是进一步探索RSSH的基本化学性质和相关的活性硫物种。由于RSSH是不稳定的，并且迅速分解成各种物种，它们在水溶液中天生就很难研究，而且通常是在原位生成的。尽管已经报道了几种产生RSSH的策略，但对于进一步开发用于生物应用的高效和受控生产RSSH的新方法的需求仍然没有得到满足。因此，新的RSSH光再生体和蛋白质过硫化试剂的开发，旨在与小分子硫醇干净地反应来产生RSSH和蛋白质半胱氨酸残基以产生PSSH，也将得到评估。这一奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。