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：
10241503
负责人：
Jared P Rutter
金额：
$ 35.12万
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/10241503
关键词：
Affect Agonist Animal Model 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 Investigation Lead Libraries Mammals Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Molecular Target Mus New Agents Organ Oryctolagus cuniculus Oxidation-Reduction Oxygen Pathologic Pharmacology Physiology Poisoning Reaction Resistance Respiration Role Series Site Specificity Testing Therapeutic Tissues Toxic effect Toxin Zebrafish animal efficacy base cell type clinical development complex IV cytochrome c oxidase experimental study folic acid metabolism glyoxylate lead candidate metabolic poison metabolomics novel pleiotropism prevent product development pyruvate dehydrogenase response success 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.

概括氰化物从根本上是一种代谢毒素。尽管它有许多已知的目标，但许多其病理后果可以归因于线粒体的抑制通过灭活电子传输链复合物IV的呼吸。鉴于此代谢在氰化物中毒的病理生理学中的重要作用，我们期望代谢的调节剂可能具有治疗性对策。在事实，该中心最近发现代谢物乙二醇深刻减轻斑马鱼，小鼠和兔子中的氰化物致死性。我们建议以此为基础通过定义该代理和其他代理的代谢功能并测试基础假设氧化还原不平衡是氰化物毒性的基础。我们进一步发现了 TCA循环的激活剂和底物也赋予氰化物的耐药性和建议进一步发展诸如治疗剂的代理商，并完成我们的高度代谢物和代谢调节剂的聚焦屏幕。我们还提出了一系列询问复杂IV抑制程度的机械实验是氰化物毒性的机制和介导该毒性的器官。这些研究将与旨在理解代谢生理的实验协同作用氰化物的毒性和对各种缓解方法的反应。我们假设对氰化物毒性和缓解代谢基础的更深入了解将告知一种合理的对策方法及其适当的应用。