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.

项目总结