Radiation protection with SOD mimetics

SOD 模拟物的辐射防护

• 批准号: 7655344
• 负责人: ZELJKO VUJASKOVIC
• 金额: $ 25.03万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7655344
• 关键词: Amino Acid Sequence; Antibodies; Antioxidants; Biological Availability; Cells; Chest; Chronic; Development; Electron Spin Resonance Spectroscopy; Ethers; Ethyl Ether; Exposure to; Goals; Grant; Hematopoietic; Hour; Injury; Ionizing radiation; Lead; Lung; Manganese; Medical; Modification; Neutrons; Normal tissue morphology; Oxidative Stress; Peptides; Photons; Plasma; Porphyrins; Production; Protein Overexpression; Radiation; Radiation Protection; Radioprotection; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Severities; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Spin Trapping; Structure of parenchyma of lung; Superoxide Dismutase; Support Groups; Syndrome; Testing; Time; Tissues; Toxic effect; Transgenic Organisms; United States National Institutes of Health; Week; base; cytokine; design; ethylpyridinium; experience; extracellular; gastrointestinal; irradiation; lung injury; manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; mimetics; mouse model; nonhuman primate; novel; prevent

The overall goal of this project is to develop a new strategy to protect, ameliorate and treat radiation (RT)-induced normal tissue injury by using a novel synthetic manganese(Mn)-porphyrins as potent scavengers of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The strategy is based on our current mechanistic studies implicating chronic oxidative stress as an important contributing factor in the development of RT-induced normal tissue injury. We hypothesize that exposure to ionizing radiation results in chronic oxidative stress which is associated with continuous production of ROS/RNS and expression/activation of damaging cytokines involved in development of RT-induced normal tissue injury. Several lines of evidence from our group support this hypothesis. Using electron spin resonance (ESR) and spin trapping we have demonstrated the presence of ROS in rat lungs 13 weeks after irradiation. In a transgenic mouse model we have shown that overexpression of extracellular superoxide dismutase (EC-SOD), an important scavenger of ROS, ameliorates RT-induced lung injury. In addition, our studies show that Mn(III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+) compound can be used to target ROS and reduce RT-induced lung damage if given prior to radiation exposure. This proposal is designed to test already established and further develop/optimize new catalytic Mn-porphyrin compounds, to document their ability to prevent/ameliorate or treat RT-induced normal tissue injury after exposure to photons or mixed neutron/photon type of ionizing radiation. With the growing threats from radiation exposure after terrorist attack, the development of effective radioprotective compounds as proposed in this project will be an important contribution for establishment of effective medical countermeasures against radiation.

该项目的总体目标是制定一种新的策略，以保护，改善和治疗辐射（RT）诱导的正常组织损伤，通过使用新型的合成锰（MN） - 孢子蛋白作为活性氧（ROS）和反应性氮种（RNS）的有效清除剂（RNS）。该策略是基于我们当前的机械研究，将慢性氧化应激视为发展的重要因素 RT诱导的正常组织损伤。我们假设暴露于电离辐射会导致慢性氧化应激，这与连续产生ROS/RN以及参与RT诱导的正常组织损伤发展的破坏性细胞因子的表达/激活有关。来自我们小组的几条证据支持这一假设。使用电子自旋共振（ESR）和自旋诱捕，我们在辐照后13周证明了ROS在大鼠肺中的存在。在转基因小鼠模型中，我们已经表明，对ROS的重要清除剂的细胞外超氧化物歧化酶（EC-SOD）的过表达可改善RT诱导的肺损伤。此外，我们的研究表明，MN（III）四甲基甲基甲虫（N-乙基吡啶-2-基）卟啉（MNTE-2-PYP5+）化合物可用于靶向ROS并减少RT诱导的肺损伤，如果在辐射暴露之前给出。该建议旨在测试已经建立的，并进一步开发/优化新的催化Mn-porphyrin化合物，以记录其在暴露于光子或混合中子/光子类型的电离辐射后预防/改善或治疗RT诱导的正常组织损伤的能力。随着恐怖袭击后辐射暴露的威胁日益加剧，有效的放射保护 该项目中提出的化合物将是建立有效的对辐射的有效医疗对策的重要贡献。