Radiation protection with SOD mimetics

本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）诱导的正常组织损伤，通过使用一种新的合成锰（Mn）-卟啉作为活性氧（ROS）和活性氮（RNS）的有效清除剂。该策略是基于我们目前的机制研究，涉及慢性氧化应激作为一个重要的促进因素，在发展中 放射治疗引起的正常组织损伤我们假设暴露于电离辐射导致慢性氧化应激，这与持续产生ROS/RNS和参与RT诱导的正常组织损伤的发展的破坏性细胞因子的表达/激活有关。我们小组的一些证据支持这一假设。用电子自旋共振（ESR）和自旋捕集，我们已经证明了存在的活性氧在大鼠肺照射后13周。在转基因小鼠模型中，我们已经表明，细胞外超氧化物歧化酶（EC-SOD），一个重要的清除活性氧，过度表达，改善RT诱导的肺损伤。此外，我们的研究表明，Mn（III）四（N-乙基吡啶鎓-2-基）卟啉（MnTE-2-PyP 5+）化合物如果在辐射暴露之前给予，则可用于靶向ROS并减少RT诱导的肺损伤。该提案旨在测试已经建立的并进一步开发/优化新的催化Mn-卟啉化合物，以记录它们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越来越大，有效的辐射防护技术的发展， 本项目中提出的化合物将为建立有效的抗辐射医学对策做出重要贡献。

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.