Radiation protection with SOD mimetics

SOD 模拟物的辐射防护

• 批准号: 7310442
• 负责人: ZELJKO VUJASKOVIC
• 金额: $ 22.69万
• 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/7310442
• 关键词: bioterrorism /chemical warfare; cooperative study; free radical scavengers; ionizing radiation; laboratory rat; lung injury; manganese; metalloporphyrins; oxidative stress; porphyrin structure; radiation dosage; radiation hazard; radiation protection; superoxide dismutase

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开发一种新的策略来保护、改善和治疗辐射(RT)所致的正常组织损伤，方法是使用一种新型的合成锰(Mn)-卟啉作为活性氧(ROS)和活性氮(RNS)的有效清除剂。这一策略是基于我们目前的机制研究，即慢性氧化应激是导致癌症发生的重要因素 放射治疗引起的正常组织损伤。我们假设，电离辐射暴露导致慢性氧化应激，这与ROS/RNS的持续产生和参与RT诱导的正常组织损伤的破坏性细胞因子的表达/激活有关。我们小组的几条证据支持这一假设。利用电子自旋共振(ESR)和自旋捕获技术，我们证实了照射后13周大鼠肺内ROS的存在。在转基因小鼠模型中，我们已经证明过表达细胞外超氧化物歧化酶(EC-SOD)，一种重要的ROS清除剂，可以改善RT诱导的肺损伤。此外，我们的研究表明，四(N-乙基吡啶-2-基)卟啉(MnTe-2-PyP5+)化合物可用于靶向ROS，减少放射治疗所致的肺损伤。这项建议旨在测试和进一步开发/优化新的催化锰卟啉化合物，以证明它们在暴露于光子或混合中子/光子类型的电离辐射后，能够预防/改善或治疗放射治疗引起的正常组织损伤。随着恐怖袭击后辐射暴露的威胁越来越大，有效的辐射防护的发展 本项目中提出的化合物将为建立有效的辐射医学对策做出重要贡献。