Hydrogen Sulfide and Carbonyl Sulfide Delivery for Biological Applications

用于生物应用的硫化氢和硫化羰输送

• 批准号: 10683153
• 负责人: Michael Pluth
• 金额: $ 32万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683153
• 关键词: Address; Alginates; Animal Model; Animals; Attention; Biological; Biological Models; Biology; Blood Vessels; Bone Regeneration; Cell Culture Techniques; Cell model; Chemicals; Defect; Disease; Engineering; Enzymes; Family; Femur; Future; Gel; Goals; Health; Human; Hydrogen Sulfide; Hydrolysis; Individual; Investigation; Knowledge; Locales; Longevity; Measures; Metabolism; Methodology; Methods; Mission; Modeling; Osteoclasts; Osteogenesis; Outcome; Play; Protein Isoforms; Public Health; Rattus; Reproducibility; Research; Research Personnel; Role; Signaling Molecule; Stimulus; Sulfides; Sulfur; System; Technology; Therapeutic; Tissues; United States National Institutes of Health; Up-Regulation; Work; biological adaptation to stress; bone; carbonate dehydratase; cellular targeting; design; disability; experimental study; immune function; in vivo; in vivo Model; innovation; insight; novel strategies; osteogenic; protective effect; recruit; regeneration model; thioester; tissue regeneration; tool

Project Summary Hydrogen sulfide (H2S) plays important roles in human health ranging from vascular biology to tissue regeneration. To advance investigations into roles, researchers often use H2S donors to directly modulate sulfide levels during experiments. Despite this broad utility, key unmet needs remain that will be addressed in this proposal. The long-term goal of this research is to develop and deploy COS/H2S donors to investigate and advance the multifaceted roles of reactive sulfur species related to human health. The overall objectives of this proposal are to broaden the platform of COS/H2S releasing motifs, to understand how different CA isoforms impact COS to H2S conversion, and to apply COS/H2S donors to in vivo models of bone regeneration. The rationale for these studies is that the functional tools for COS/H2S delivery and a greater understanding of differential CA isoform activity toward COS hydrolysis will enable future applications in which COS/H2S release is targeted to systems where key CA isoforms are present and H2S is known to play a protective effect. The proposed investigations include three specific aims: (1) Expansion, refinement, and application of COS/H2S releasing platforms; (2) Investigation in to the differential CA isoform activity toward COS hydrolysis; and (3) Application of COS/H2S donors to bone regeneration. This proposal builds from prior work establishing that COS releasing molecules can function as H2S donors due to the rapid enzymatic conversion of COS to H2S by carbonic anhydrase (CA). In Aim 1, new chemical approaches are used to enable COS/H2S delivery, expand the dynamic range and palette of traceable COS/H2S donors, and provide amplified release. In Aim 2, the hydrolytic activity of individual CA isoforms toward COS and model thioester/thionoester substrates are investigated to understand isoform differences in CA efficiency toward COS hydrolysis. In Aim 3, the developed COS/H2S donors are used to investigate the role of H2S in cell and animal models of bone regeneration. This approach is innovative because it provides new approaches to COS/H2S delivery that address key unmet needs in the field and provides the first insights into the differential activity of CA isoforms for COS to H2S conversion. Moreover, the proposed applications in bone regeneration are innovative because they not only leverage the protective effects of H2S and high local activity of CA during osteogenesis, but also leverages the underutilized connection of H2S with Ca2+ recruitment in osteoclasts. The proposed research is significant because it provides new approaches that directly address key limitations in the field, including amplified release systems, trackable donors, and analyte replacement methodologies. In addition, the proposed research provides the first insights into CA isoform differences for COS to H2S conversion, which will be leveraged in model systems relevant to human health in which both CA activity and H2S delivery are important. Successful completion of the proposed Aims will provide a positive impact in the field of H2S biology and will result a greater understanding of the roles of COS/H2S in human health.

项目摘要 硫化氢（H2S）在人类健康中起重要作用，从血管生物学到组织 再生。为了推进对角色的研究，研究人员经常使用H2S供体直接调节硫化物 实验中的水平。尽管有这种广泛的效用，但仍将解决的关键未满足需求将在此解决 提议。这项研究的长期目标是开发和部署COS/H2S捐助者来调查和 推进与人类健康有关的反应性硫种类的多方面作用。总体目标 建议将扩大COS/H2S释放图案的平台，以了解不同的CA同工型 对H2S转化的影响，并将COS/H2S供体应用于骨再生的体内模型。这 这些研究的理由是COS/H2S交付的功能工具以及对 差异Ca同工型对COS水解的活性将实现COS/H2S释放的未来应用 针对存在关键的CA同工型的系统，并且已知H2S具有保护作用。这 拟议的调查包括三个具体目的：（1）COS/H2S的扩展，改进和应用 释放平台； （2）研究对CO水解的差异Ca同工型活性； （3） 将COS/H2S供体应用于骨再生。该建议是由先前的工作建立的，确定了COS 释放分子可以作为H2S供体起作用，因为COS迅速转化为H2S 碳酸酐酶（CA）。在AIM 1中，使用新的化学方法来启用cos/h2s交付，扩展 可追溯COS/H2S供体的动态范围和调色板，并提供放大的释放。在AIM 2中，水解 研究了单个CA同工型对COS和模型硫酯/Thionoester底物的活性。 了解CA效率在COS水解方面的同工型差异。在AIM 3中，开发的cos/h2s 供体用于研究H2S在骨再生的细胞和动物模型中的作用。这种方法是 创新性，因为它提供了cos/h2s交付的新方法，以解决现场未满足的关键需求 并为CO与H2S转换的CA同工型的差异活动提供了第一个见解。而且， 提议的骨骼再生应用具有创新性，因为它们不仅利用了保护性 H2S和成骨过程中CA的高局部活动的影响，但也利用了未充分利用的连接 在破骨细胞中具有Ca2+募集的H2S的。拟议的研究很重要，因为它提供了新的 直接解决该领域关键限制的方法，包括放大的释放系统，可跟踪 捐助者和分析物替代方法。此外，拟议的研究提供了第一个见解 进入CO与H2S转换的CA同工型差异，该差异将在与 CA活动和H2S分娩都很重要的人类健康。成功完成拟议的 目标将在H2S生物学领域产生积极的影响，并将对角色有更深入的了解 人类健康中的cos/h2s。