Generation and Reactivity of Reactive Sulfur Species

有了这个奖项，化学结构，动力学机制-B计划继续支持约翰霍普金斯大学化学系教授约翰·托斯卡诺的工作。该研究将涉及生物相关的活性硫物种的产生和反应性，包括氢过硫化物（RSSH）。硫化氢（H2S）是一种内源性产生的小分子信号传导剂，其多种生理效应已被充分证明。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，H2S的生物活性可能归因于RSSH，其已被报道参与蛋白质半胱氨酸残基（PSH）的修饰以产生蛋白质氢过硫化物（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，已显示蛋白质过硫化在神经障碍如阿尔茨海默病、帕金森病和亨廷顿病中失调和减少。这项研究将为研究生和本科生提供广泛，全面的培训，为他们在工业和学术界的未来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事项，因为以前的学生已经表示，这方面的经验是他们的大学生涯的亮点，并在澄清他们的兴趣和准备他们未来的研究是有用的。一个综合的，放学后的科学外展经验，高中学生集中在化学/生物接口也将developed.Despite越来越多的证据RSSH在生理氧化还原信号的作用，RSSH的生物相关化学仍然是相对知之甚少。预测RSSH的生物学功能的一种方法是了解它们的基本化学。因此，建议的研究重点之一是进一步探索RSSH和相关的活性硫物种的基本化学性质。由于RSSH是不稳定的，并迅速分解成各种物种，它们是固有的难以在水溶液中研究，通常在原位产生。尽管已经报道了几种RSSH产生的策略，但对于进一步开发用于生物应用的RSSH的有效和受控生产的新方法仍然存在未满足的需求。因此，新型RSSH前体和蛋白质过硫化试剂的开发也将得到评估。这些试剂设计用于与小分子硫醇清洁地反应以产生RSSH，与蛋白质半胱氨酸残基清洁地反应以产生PSSH。该奖项反映了NSF的法定使命，并被认为值得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来支持。

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.