Chemical Tools for Delivery and Detection of Biological Hydrogen Sulfide

用于输送和检测生物硫化氢的化学工具

• 批准号: 9330883
• 负责人: Michael Pluth
• 金额: $ 27.1万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330883
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Atherosclerosis; Biochemical; Biochemistry; Biological; Biology; Characteristics; Chemicals; Communities; Complex; Confusion; Coupling; Data; Detection; Development; Diabetes Mellitus; Dose; Erectile dysfunction; Fluorescence Microscopy; Functional Imaging; Germ-Free; Goals; Health; Human; Hydrogen Sulfide; Hypertension; Image; Inflammation; Investigation; Ion Channel; Knowledge; Lead; Light; Locales; Measurement; Mediator of activation protein; Methods; Microbe; Mission; Molecular Target; Monitor; Nerve Degeneration; Odors; Optics; Outcome; Physiological; Play; Production; Proteins; Public Health; Reaction; Regulation; Reporter; Reporting; Research; Research Design; Research Support; Resolution; Role; Sepsis; Signal Transduction; Signaling Protein; Sulfhydryl Compounds; Testing; Time; Transition Elements; Translating; Tube; United States National Institutes of Health; Work; Zebrafish; base; biological systems; chromophore; design; disability; egg; gut microbiota; host-microbe interactions; infancy; innovation; insight; microbial; microbial colonization; microbial community; microbial host; microbiota; public health relevance; scaffold; sensor; spatiotemporal; tool

 DESCRIPTION (provided by applicant): The long-term goal of this research is to develop and apply purpose-inspired chemical tools for detecting, quantifying, and delivering biological hydrogen sulfide (H2S). Hydrogen sulfide is now accepted as an important physiological mediator and signaling agent, joining NO and CO as an endogenous gasotransmitter. H2S plays important roles in various conditions associated with human health including diabetes, hypertension, atherosclerosis, inflammation, neurodegeneration, sepsis, and asthma. Upon enzymatic production, H2S exerts its action on different molecular targets, including ion channels and signaling proteins through reaction with protein thiols and transition-metal centers. Despite the diverse and important biochemical roles of H2S, limited methods are available for detecting, quantifying, or delivering biologically-relevant H2S concentrations. Although many of the reported chemical tools for H2S work well in non-biological settings, few of these tools have proven sufficiently sharp to make the transition from test tubes to real biological contexts. To address these unmet needs, the objectives in this proposal are to develop and refine purpose-inspired chemical tools for biological H2S detection, quantification, and delivery and to apply these tools to investigate host-microbial interactions in live zebrafish. The rational for this wor is that successful completion of the proposed Aims will provide robust chemical tools and provide a positive impact toward studying and understanding the multifaceted roles of H2S in biology. Motivated by proof-of-concept preliminary results supporting the research design, specific aims include: 1) Development and application of selective reporters for H2S; 2) Development and application of traceable, slow-release H2S donors; 3) Functional imaging of H2S and microbial colonization dynamics in zebrafish. Objectives outlined in the first Aim include new platforms to translate H2S imaging into biologically-relevant concentration ranges by using bright pH insensitive chromophores, targeted H2S sensors, and signal amplification methods to lower the detection limits of H2S probes. Objectives outlined in the second Aim include new innovative strategies for coupling H2S delivery with an optical readout to facilitate non- invasive, real-time monitoring of H2S delivery to bridge the gap between cuvette- and context-based measurements of H2S release. Objectives outlined in the third Aim include imaging H2S production in conventional, germ-free, and monobacterial zebrafish, and determining the role of H2S on microbial gut colonization dynamics. The proposed research is significant because the outlined approaches directly address current unmet needs and limitations in the field related to H2S imaging, quantification, and delivery. Successful completion of the proposed Aims will provide a positive impact in the field of H2S biochemistry and will result a greater understanding of the important and multifaceted roles of H2S associated with human health.

 描述（由申请人提供）：本研究的长期目标是开发和应用特定用途的化学工具来检测、定量和传递生物硫化氢 (H2S)。硫化氢现在被认为是一种重要的生理介质和信号剂，与 NO 和 CO 一起作为内源性气体递质。 H2S 在与人类健康相关的各种疾病中发挥着重要作用，包括糖尿病、高血压、动脉粥样硬化、炎症、神经退行性变、败血症和哮喘。酶促产生后，H2S 通过与蛋白质硫醇和过渡金属中心反应，对不同的分子靶标发挥作用，包括离子通道和信号蛋白。尽管 H2S 具有多种重要的生化作用，但可用于检测、定量或提供生物学相关 H2S 浓度的方法有限。尽管许多报道的 H2S 化学工具在非生物环境中效果良好，但很少有这些工具被证明足够锋利，能够从试管过渡到真实的生物环境。为了解决这些未满足的需求，本提案的目标是开发和完善用于生物 H2S 检测、定量和传递的特定化学工具，并应用这些工具来研究活体斑马鱼的宿主-微生物相互作用。这项工作的理由是，成功完成拟议的目标将提供强大的化学工具，并对研究和理解 H2S 在生物学中的多方面作用产生积极影响。在支持研究设计的概念验证初步结果的推动下，具体目标包括： 1) H2S 选择性报告基因的开发和应用； 2）可追溯、缓释H2S供体的开发与应用； 3) 斑马鱼中 H2S 和微生物定植动态的功能成像。第一个目标中概述的目标包括新平台，通过使用明亮的 pH 不敏感发色团、靶向 H2S 传感器和信号放大方法，将 H2S 成像转化为生物相关的浓度范围，以降低 H2S 探针的检测限。第二个目标中概述的目标包括将 H2S 输送与光学读数相结合的新创新策略，以促进对 H2S 输送的非侵入性实时监测，从而弥合基于比色皿和基于环境的 H2S 释放测量之间的差距。第三个目标中概述的目标包括对常规、无菌和单细菌斑马鱼中的 H2S 产生进行成像，并确定 H2S 对微生物肠道定植动态的作用。拟议的研究意义重大，因为概述的方法直接解决了与 H2S 成像、量化和输送相关领域当前未满足的需求和限制。成功完成拟议目标将对硫化氢生物化学领域产生积极影响，并使人们更好地了解硫化氢与人类健康相关的重要和多方面的作用。