CAREER: New Chemical Tools for Probing the Biological Significance of Hydrogen Sulfide and Hydrogen Selenide

职业：探索硫化氢和硒化氢生物学意义的新化学工具

• 批准号: 2143826
• 负责人: John Lukesh
• 金额: $ 62.5万
• 依托单位: Wake Forest University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2143826&HistoricalAwards=false
• 关键词: CAREER; New; Chemical; Tools; Probing; CAREER; New; Chemical; Tools; Probing

This award is funded in part under the American Rescue Plan Act of 2021 (Public Law 117-2).With support of the Chemistry of Life Processes Program in the Division of Chemistry, John Lukesh of Wake Forest University is developing new chemical tools to investigate the biological significance of hydrogen sulfide (H2S) and hydrogen selenide (H2Se). Given that both gases were historically dismissed as toxic pollutants with little relevance to human biology, a comprehensive understanding of their biological functions, cellular targets, and production and metabolism remains elusive. The overall goal of this proposal is to answer these specific questions through molecular design and the development of new molecular scaffolds that effectively detect or deliver H2S and H2Se under biologically relevant conditions. Students engaged in these efforts will be exposed to a wide-variety of topics and techniques at the ever-widening interface of chemistry and biology as they unlock a new frontier to the redox signaling community. This program also integrates a multi-tiered approach aimed at connecting with the local community of Winston-Salem, NC. These efforts include the development of fun and interactive chemistry lectures for local middle school students and the active recruitment of underrepresented minority college students to research positions at Wake Forest University. To facilitate new investigations into the prevalence and physiological significance of H2S and H2Se, this project aims to engineer new chemical tools to assist in the delivery or detection of both gases under biologically relevant conditions. Specifically, fundamentally new chemistry will be employed to selectively release H2S from sulfur-containing motifs via an analyte-triggered cyclization reaction. This unique mechanistic pathway will be used to unlock a family of donors that have the potential to advance the field of sulfide signaling research through their ability to target specific tissues and organelles; selectively respond to stimuli upregulated in disease; and self-report their real time delivery of H2S through concurrent fluorophore assembly. This project also represents a pioneering effort to generate new donors and reaction-based probes specific to H2Se. Given the scarcity of such compounds, this new chemistry has the potential to accelerate molecular signaling research, and to spark an emerging area of science aimed at exploring the chemical biology and innate physiological functions of H2Se, including its propensity to promote oxidative post-translational modifications.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.

该奖项是根据2021年《美国救援计划法》（公法117-2）的部分资助。在化学过程中支持化学过程的化学过程，威克森林大学的约翰·卢克什（John Lukesh）正在开发新的化学工具，以研究硫化氢（H2S）和Hydrogen selenide（H2SE）的生物学意义。鉴于这两种气体在历史上被认为是有毒污染物，与人类生物学无关的有毒污染物，因此对其生物学功能，细胞靶标，生产和代谢的全面了解仍然难以捉摸。该提案的总体目标是通过分子设计和新分子支架的发展回答这些特定问题，这些脚手架在生物学上相关的条件下有效地检测或传递H2S和H2SE。从事这些努力的学生将在化学和生物学的不断扩大的界面上接触到广泛的主题和技术，因为他们向氧化还原信号社区解锁了新的边界。该计划还集成了一种多层方法，旨在与北卡罗来纳州温斯顿·塞勒姆当地社区建立联系。这些努力包括为当地中学生开发有趣和互动化学讲座，以及积极招募代表性不足的少数民族大学生来研究维克森林大学的研究职位。为了促进对H2S和H2SE的患病​​率和生理意义的新调查，该项目旨在设计新的化学工具，以帮助在生物学相关条件下交付或检测两种气体。具体而言，从根本上讲，新的化学将通过分析物触发的环化反应选择性地从含硫基序中选择性释放H2。这种独特的机械途径将用于解锁捐赠者家族，这些捐赠者有可能通过靶向特定组织和细胞器的能力来推进硫化物信号研究领域。有选择地应对疾病上调的刺激；并通过并发的荧光团组件自我报告H2的实时交付。该项目还代表了生成新捐助者和基于反应的探针特有的探针的开创性努力。考虑到这种化合物的稀缺性，这种新的化学反应有可能加速分子信号传导研究，并引发旨在探索H2SE的化学生物学和先天生理功能的科学领域影响审查标准。