权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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气体递质，单微摩尔浓度或更低浓度正积极地用于临床应用。三种药物基于硫化氢释放的药物正在进行I期或II期临床试验。虽然地点在哪里细胞内的外源性硫化氢分配可以使用几种两步标记方法来追踪，不能追踪外源性硫化氢在组织或动物模型中的位置。这限制了开发基于硫化氢缓慢释放的疗法，因为一旦硫化氢释放，被施用于动物或组织。长期目标是研究外源性硫化氢在体内运输和积累。本应用程序的总体目标是合成化学品广泛用于添加外源性硫化氢，因此这些化学品释放放射性 35 S标记的硫化氢，这将使它首次在组织和动物水平上被追踪。的中心假设是，35 S标记的硫酸盐可以转化为几种关键的化学物质，硫化氢对不同刺激的反应，以及35 S标记的浓度和量可以合理控制硫化氢。该提案建立在其他人使用35 S的先前工作的基础上标记蛋氨酸、半胱氨酸和其他化学物质，以研究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。尽管使用这些35 S的成功标记的化学品，没有人描述过缓慢释放35 S标记的氢的化学品的合成硫化物，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跟踪外源性硫化氢在组织和动物模型中的分布，探讨外源性硫化氢在动物模型中治疗疾病作用的来源。的中心假设将通过追求两个具体目标进行测试：1）识别合成GYY的反应- 4137、二烷基二硫代磷酸盐、笼状过硫醇和DTT在受控条件下释放35 S标记的硫化氢速率和剂量;以及2）确定合成二烯丙基三硫化物和半胱氨酸的三硫化物的反应，谷胱甘肽，其在硫醇存在下将释放35 S标记的硫化氢。该研究在在申请人看来，这种应用是创新的，因为它挑战了跟踪通过合成化学物质来定位外源性硫化氢，这将使其能够在组织和动物层面的研究。这个建议结合了闪烁和光学显微镜放射自显影，用于成像35 S标记的氨基酸与化学品的第一次合成，缓慢释放35 S标记硫化氢，解决生物学中的关键问题。拟议的研究是意义重大，因为它将推进已经在进行的研究，以了解外源性H2S的影响，以更快地开发这些化学品的临床应用。