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Slow release of isotopically labelled hydrogen sulfide to track its location in animals and tissues

缓慢释放同位素标记的硫化氢以追踪其在动物和组织中的位置

基本信息

批准号：
10382220
负责人：
NED B BOWDEN
金额：
$ 7.59万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382220
关键词：
Adhesions Affect Alzheimer&apos s Disease Amino Acids Animal Disease Models Animal Model Animals Arthritis Autoradiography Biology Cell membrane Cells Chemicals Cysteine Degenerative polyarthritis Development Disease Dose Enzymes Fluorescence Spectroscopy Glaucoma Glutathione Goals Half-Life Heart failure Human Hydrogen Sulfide Hypertension Image Individual Integral Membrane Protein Investigation Isotope Labeling Label Leukocytes Location Malignant Neoplasms Mass Spectrum Analysis Medicine Methionine Methods Myocardial Infarction Neuroglia Neurons Organ Outcome Parkinson Disease Pathway interactions Persons Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Proteins Public Health Radioactive Reaction Reactive Oxygen Species Reagent Research Rheumatoid Arthritis Scientist Sepsis Signal Pathway Stimulus Structure Sulfate Sulfhydryl Compounds Testing Time Tissue Model Tissues Work animal tissue base biological adaptation to stress cell type chemical release chemical synthesis clinical application clinical development diallyl trisulfide endoplasmic reticulum stress in vivo innovation light microscopy mouse model neuron loss novel therapeutics persulfides phase II trial radiotracer response success therapy development

项目摘要

Hydrogen sulfide is a key gasotransmitter in human cells, and the addition of exogenous hydrogen sulfide at single micromolar or lower concentrations is actively being explored for clinical applications. Three drugs based on the release of hydrogen sulfide are in phase I or II clinical trials. Although the location of where exogenous hydrogen sulfide partitions inside of cells can be tracked using several two-step tagging methods, tracking the location of exogenous hydrogen sulfide in tissue or animal models cannot be done. This limits the development of therapies based on the slow release of hydrogen sulfide because it cannot be tracked once it is administered to an animal or tissue. The long-term goal is to investigate the mechanisms of how exogenous hydrogen sulfide is transported and accumulates in the body. The overall objective of this application is to synthesize chemicals widely used to add exogenous hydrogen sulfide, so these chemicals release radioactive 35S labelled hydrogen sulfide which will allow it to be tracked on a tissue and animal level for the first time. The central hypothesis is that 35S labeled sulfate can be converted into several key chemicals that release hydrogen sulfide in response to different stimuli, and that the concentration and amount of 35S labelled hydrogen sulfide can be rationally controlled. This proposal builds on prior work by others that used 35S labelled methionine, cysteine, and other chemicals to investigate where they partitioned in animal and tissue models using scintillation and light microscopy autoradiography. Despite the success of the use of these 35S labelled chemicals, no one has described the synthesis of chemicals that slowly release 35S labelled hydrogen sulfide despite its importance in medicine. The rationale for completing this work is that it will allow scientists to track where exogenous hydrogen sulfide partitions in tissue and animal models for the first time to thoroughly investigate the origins of the effect of exogenous hydrogen sulfide in treating diseases in animal models. The central hypothesis will be tested by pursuing two specific aims: 1) Identify the reactions to synthesize GYY- 4137, dialkyldithiophosphates, caged perthiols, and DTT to release 35S labelled hydrogen sulfide at controlled rates and doses; and 2) Identify the reactions to synthesize diallyl trisulfide and trisulfides of cysteine and glutathione that will release 35S labelled hydrogen sulfide in the presence of thiols. The research proposed in this application is innovative, in the applicant's opinion, because it challenges the status quo of tracking the location of exogenous hydrogen sulfide by the synthesis of chemicals that will allow it to be tracked on the tissue and animal levels for the first time. This proposal combines scintillation and light microscopy autoradiography that were used to image 35S labelled amino acids with the first synthesis of chemicals to slowly release 35S labelled hydrogen sulfide to solve a key problem in biology. The proposed research is significant because it will advance research already underway to understand the effects of exogenous H2S and to more rapidly develop clinical applications of these chemicals.

硫化氢是人体细胞中的一种关键的气体传递物质，外源硫化氢在单一微摩尔或更低浓度的药物正被积极探索用于临床应用。三种药物基于硫化氢的释放正在进行I期或II期临床试验。虽然地点在哪里可以使用几种两步标记方法来跟踪细胞内的外源硫化氢分区，追踪外源性硫化氢在组织或动物模型中的位置是不可能的。这限制了基于硫化氢缓慢释放的治疗方法的开发，因为它一旦释放就无法追踪给动物或组织注射。长期目标是研究外生性是如何硫化氢在体内运输和积累。此应用程序的总体目标是合成化学物质广泛用于添加外源硫化氢，因此这些化学物质释放出放射性 35S标记了硫化氢，这将使它第一次能够在组织和动物水平上被追踪。这个中心假设是，标记硫酸盐的35S可以转化为几种关键的化学物质，释放出来硫化氢对不同刺激的响应，以及标记的35S的浓度和量硫化氢是可以合理控制的。这项建议建立在其他使用35的人之前的工作基础上标记蛋氨酸、半胱氨酸和其他化学物质，以调查它们在动物和组织中的分配位置模型使用闪烁和光学显微镜放射自显影。尽管这些35的使用取得了成功标记的化学物质，没有人描述缓慢释放35S标记氢气的化学物质的合成硫化物，尽管它在医学上很重要。完成这项工作的理由是，它将使科学家能够首次追踪外源性硫化氢在组织和动物模型中的位置以彻底探讨外源性硫化氢在动物模型中治疗疾病的作用来源。这个中心假设将通过追求两个具体目标来检验：1)确定合成GYY-的反应- 4137，二烷基二硫代磷酸盐，笼状硫醇和DTT在受控下释放35S标记的硫化氢速率和剂量；以及2)确定合成半胱氨酸的二烯丙基三硫和三硫的反应，以及在硫醇存在的情况下释放35S标记的硫化氢的谷胱甘肽。这项研究建议在在申请人看来，这项申请是创新的，因为它挑战了跟踪通过合成化学物质来定位外源硫化氢，使其能够在组织和动物水平的第一次。这一提议结合了闪烁和光学显微镜。放射自显影用于成像35S标记的氨基酸，首次合成化学物质以缓慢释放标记为硫化氢的35S，以解决生物学中的一个关键问题。拟议的研究是意义重大，因为它将推动已经在进行的研究，以了解外源硫化氢和以更快地开发这些化学物质的临床应用。