Discovering novel metabolic targets to mitigate cyanide toxicity

发现减轻氰化物毒性的新代谢靶点

基本信息

批准号：
10671673
负责人：
Jared P Rutter
金额：
$ 35.35万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671673
关键词：
Affect Agonist Antidotes Binding Biological Brain Carbon Cell Culture Techniques Citric Acid Cycle Clinical Collaborations Coupled Cyanides Cytosol Data Development Dose Drug Formulations Drug Kinetics Enzymes Foundations Functional disorder Genetic Goals Heart Heme Iron Homeostasis Intervention Libraries Mammals Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Molecular Target Mus New Agents Organ Oryctolagus cuniculus Oxidation-Reduction Oxygen Pathologic Physiology Poisoning Reaction Reproducibility Resistance Respiration Role Series Site Specificity Testing Therapeutic Tissues Toxic effect Toxin Zebrafish animal efficacy cell type clinical development complex IV cytochrome c oxidase experimental study folic acid metabolism glyoxylate lead candidate metabolic poison metabolomics model organism novel pharmacologic pleiotropism prevent product development pyruvate dehydrogenase response success synergism tool

项目摘要

Summary Cyanide is fundamentally a metabolic toxin. Although it has many known targets, many of its pathological consequences can be ascribed to inhibition of mitochondrial respiration through inactivation of Complex IV of the electron transport chain. Given this prominent role of metabolism in the pathophysiology of cyanide poisoning, we expect that modulators of metabolism might have potential as therapeutic countermeasures. In fact, this Center has recently discovered that the metabolite glyoxylate profoundly mitigates cyanide lethality in zebrafish, mice and rabbits. We propose to build upon this foundation by defining the metabolic functions of this and other agents and testing the hypothesis that redox imbalance underlies cyanide toxicity. We have further discovered that activators and substrates of the TCA cycle also confer cyanide resistance and propose to further develop such agents as therapeutics as well as complete our highly focused screen of metabolites and metabolic modulators. We also propose a series of mechanistic experiments to interrogate the extent to which Complex IV inhibition is the mechanism of cyanide toxicity and the organs that mediate that toxicity. These studies will synergize with experiments aimed at understanding the metabolic physiology of cyanide toxicity and the response to various mitigating approaches. We hypothesize that a deeper understanding of the metabolic basis of cyanide toxicity and mitigation will inform a rational approach to countermeasures and their appropriate application.

概括氰化物本质上是一种代谢毒素。尽管它有许多已知目标，但许多其病理后果可归因于线粒体的抑制通过电子传递链复合体 IV 的失活来进行呼吸作用。鉴于此我们预计代谢在氰化物中毒的病理生理学中发挥着重要作用新陈代谢调节剂可能具有作为治疗对策的潜力。在事实上，该中心最近发现代谢物乙醛酸对减轻氰化物对斑马鱼、小鼠和兔子的致死率。我们建议在此基础上通过定义该药物和其他药物的代谢功能并测试假设氧化还原失衡是氰化物毒性的基础。我们进一步发现 TCA 循环的活化剂和底物也具有抗氰化物的能力建议进一步开发此类药物作为治疗剂，并完成我们的高度研究代谢物和代谢调节剂的重点筛选。我们还提出了一系列探究复合物 IV 抑制作用的程度的机制实验氰化物毒性的机制以及介导该毒性的器官。这些研究将与旨在了解代谢生理学的实验相协同氰化物毒性以及对各种缓解方法的反应。我们假设更深入地了解氰化物毒性和缓解的代谢基础将提供合理的对策及其适当应用。