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）在人体健康中起着重要的作用，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供体来直接调节硫化物 实验中的水平。尽管有这种广泛的效用，但仍有一些关键的未满足的需求，将在本报告中加以解决。 提议本研究的长期目标是开发和部署COS/H2S供体， 促进与人类健康相关的活性硫物质的多方面作用。这一总体目标 我们的建议是拓宽COS/H2S释放基序的平台，了解不同的CA异构体 影响COS向H2S转化，并将COS/H2S供体应用于骨再生的体内模型。的 这些研究的基本原理是，COS/H2S输送的功能工具和对 不同的CA同种型对COS水解的活性将使未来的应用成为可能，其中COS/H2S释放 针对存在关键CA亚型且已知H2S起保护作用的系统。的 本文提出的研究工作包括三个具体目标：（1）COS/H_2S催化剂的扩展、改进和应用 释放平台;（2）研究CA同工型对COS水解的差异活性;以及（3） COS/H2S供体在骨再生中的应用该提案基于先前的工作， 释放分子可以作为H2S供体，这是由于COS通过酶促反应快速转化为H2S， 碳酸酐酶（CA）。在目标1中，使用新的化学方法来实现COS/H2S输送，扩大 可追踪COS/H2S供体的动态范围和调色板，并提供放大释放。在目标2中， 研究了单个CA同工型对COS和模型硫酯/硫酸酯底物的活性， 了解CA对COS水解效率的异构体差异。在目标3中，开发了COS/H_2S 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 创新，因为它提供了COS/H2S交付的新方法，解决了该领域未满足的关键需求 并提供了第一个洞察到的差异活性的CA异构体COS到H2S的转化。此外，委员会认为， 所提出的骨再生应用是创新的，因为它们不仅利用了保护性的 H2S和CA在骨生成过程中的高局部活性的影响，但也利用了未充分利用的连接 H2S与破骨细胞中Ca 2+的募集。这项研究意义重大，因为它提供了新的 直接解决该领域关键限制的方法，包括放大释放系统，可追踪 供体和分析物替代方法。此外，拟议的研究提供了第一个见解， 将COS转化为H2S的CA亚型差异，这将在与以下相关的模型系统中利用： CA活性和H2S释放对人类健康都很重要。圆满完成拟议的 目的将在H2S生物学领域产生积极影响，并将导致对H2S生物学的作用有更好的理解。 COS/H2S对人体健康的影响。