EXPERIMENTAL THERAPEUTICS & REACTIVE METABOLITE INJURY

实验治疗

• 批准号: 3096220
• 负责人: JERRY R. MITCHELL
• 金额: $ 53.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3096220
• 关键词: biotransformation; cell death; oxygen therapy; toxin metabolism

The program project has two objectives. The first is the identification of the functional and structural mechanisms responsible for reactive metabolite-induced lethal cell injury. The goals of Project I, "Final Common Pathway for Reactive Metabolite Injury: Abnormal Ca2+ Homeostasis," are to complete the work in progress documenting that lesions at calcium regulatory sites mediate reactive metabolite-induced hepatic necrosis (acetaminophen, bromobenzene, CC14, diquat) and to investigate the role of changes in membrane calcium permeability versus calcium- ATPase activity in the plasma membrane and endoplasmic reticulum lesions. The goals of Project II, "Chemical mechanisms of Lipid peroxidation and Thiol Oxidation in Oxidative Reactive metabolite Injury," are to define chemically the mechanisms of lipid membrane peroxidation and protein thiol oxidation after diquat and acetaminophen, to determine the effects of diquat-initiated, reactive oxygen-mediated hepatic necrosis on hepatic iron complexes and metabolism in vivo and to determine the effects of desferrioxamine and ferrous sulfate of these parameters. The goals of Project III, "Studies of Alkylating Reactive Metabolites Using Novel Mass Spectrometric Techniques," are to characterize the structure of peptide adducts and reaction mechanisms of substituted furans and to utilize this knowledge to elucidate principles for the covalent binding of electrophiles based on the "hardness" of their electrophilicity and on their ability to serve as substrates for GSH-S-transferases. The goals of Project IV, "Oxygen Metabolite-Initiated Injury in Oxygen Therapy and in Ischemia- Reflow condition," are to determine the presence of lipid peroxidation or protein thiol oxidation products and their pathogenetic importance is reactive oxygen injury and to determine the presence of vasoactive or chemotactic eicosanoid products and the pathogenetic importance of reactive oxygen serving as a calalyst to stimulate or modulate eicosanoid formation. The second objective of the PPG is the transfer of basic discoveries and methodologies in Projects I-lV to clinical investigation and applications in experimental therapeutics (Project V: "Oxygen Metabolite-Initiated Injury in Neonates;" Project VI: "Oxygen Metabolite-Initiated Injury in Adult Critical Care Medicine;" Project VII: "GSH Homeostasis and GSSG Reductase Inhibition after BCNU Therapy in Man"). The knowledge obtained in the basic studies should provide important new insights into the fundamental mechanisms responsible for lethal cell injury by reactive metabolites. The clinical studies should demonstrate and define the relevance of these mechanisms for improved therapy of drug and ischemia-induced diseases.

该项目有两个目标。 首先是 确定功能和结构机制 负责反应性代谢物诱导的致死性细胞损伤。 项目I的目标是“反应性的最终通用途径”， 代谢损伤：异常钙稳态，”是为了完成 正在进行的工作记录了钙调节系统的病变， 位点介导反应性代谢物诱导的肝坏死 （对乙酰氨基酚，溴苯，CC 14，敌草快），并研究 膜钙渗透性变化与钙离子浓度变化的关系 质膜和内质网中的ATP酶活性 病变 项目II的目标，“脂质的化学机制 氧化反应性代谢物中的过氧化和巯基氧化 损伤”是化学定义的机制，脂质膜 过氧化和蛋白硫醇氧化后敌草快， 对乙酰氨基酚，以确定敌草胺引发的影响， 活性氧介导的肝坏死对肝铁复合物的影响 和体内代谢，并确定 去铁胺和硫酸亚铁的这些参数。 的目标 项目III，“研究烷基化反应性金属， 新的质谱技术，”是表征 肽加合物的结构和取代基的反应机理 并利用这一知识阐明原则， 亲电体的共价结合基于“硬度”， 它们的亲电性和它们作为底物的能力 GSH-S-转移酶。 项目四的目标，“氧气 氧疗和缺血中代谢物引发的损伤- 回流条件”是为了确定脂质的存在 过氧化或蛋白质硫醇氧化产物及其 致病的重要性是活性氧损伤，并确定 血管活性或趋化性类花生酸产物的存在， 活性氧作为一种 催化剂以刺激或调节类二十烷酸形成。 第二 PPG的目标是转移基本发现， 项目I-IV中的方法用于临床研究， 在实验治疗学中的应用（项目V：“氧气 新生儿代谢物引发的损伤;”项目VI：“氧气 代谢物致损伤在成人重症医学中的应用 项目七：“谷胱甘肽稳态和GSSG还原酶抑制后， BCNU Therapy in Man”）。 在基础研究中获得的知识 应该提供重要的新见解的基本 反应性细胞损伤的机制 代谢物。 临床研究应证明和定义 这些机制对于改善药物治疗的相关性， 缺血性疾病。