New small molecule targets for radiation protection

在“脏弹”爆炸后，或在一些不那么险恶但同样严重的核事故后，可以预期大多数随之而来的伤亡者将受到相对较低剂量的照射。因此，紧急服务将不得不治疗大量的受害者（包括受影响的公众，紧急救援人员和医务人员），其中由于“旁观者效应”而造成的组织损伤至关重要。辐射后活性氧和活性氮物质（ROS和RNS）的产生是一种慢性现象，在接受剂量后几分钟内开始。我们最近获得的证据，从后照射大鼠组织持续生产的超氧自由基天后，低剂量已被终止。由于锰超氧化物歧化酶（MnSOD）在预辐照组织中的表达显著改善了该效应，因此明确暗示了超氧化物产生的位点。此外，容易检测到的生产过氧亚硝酸根阴离子在postirradiated组织的内源性一氧化氮合酶（NOS）的刺激后，表明这种强大的氧化剂的第二代是一个主要后果的超氧化物水平升高。在取自未经辐照动物的对照组织中未观察到这些效应。具体目的：1）确定在以下的最初几个小时内初始超氧化物产生的线粒体位点（建议为mtNOS）： 2）确定ROS/RNS（建议为复合物III）导致进一步（慢性）超氧化物生成（“后期过程"）的线粒体损伤位点，并设计使这些中心失活的策略; 3）确定过氧亚硝酸盐和过氧化氢生成在电子传递链（ETC）辐照后损伤中的相对重要性。在这些具体目标的框架内，建议开发和测试推定的药物，旨在防止在线粒体位点形成关键的ROS/RNS，这些位点被确定为负责其生成。除了功效， 将评价这些化合物的可能毒性（在ETC水平上），以促进随后在迭代合成和测试中产生的其它候选药物的特性的改进。

Following detonation of a "dirty bomb," or some less sinister but equally serious nuclear accident, the majority of the ensuing casualties can be anticipated to receive relatively low-dose exposures. Consequently, emergency services will have to treat large numbers of victims (including the affected public, emergency responders and medical staff) where developing tissue damage due to "bystander effects" is of paramount importance. Post-irradiation production of reactive oxygen and reactive nitrogen species (ROS and RNS) is a chronic phenomenon that starts within minutes of the dose being received. We have recently obtained evidence from post-irradiated rat tissue for sustained production of superoxide radical days after low-level doses have been terminated. The mitochondrion is clearly implicated as the site of superoxide production as manganese supeoxide dismutase (MnSOD) expression in the pre-irradiated tissue significantly ameliorates the effect. Furthermore, the readily detectable production of peroxynitrite anion in postirradiated tissue following the stimulation of endogenous nitric oxide synthase (NOS) indicates the secondary generation of this powerful oxidant to be a major consequence of the elevated superoxide level. None of these effects are observed in control tissue taken from unirradiated animals. Specific Aims: 1) Identify the mitochondrial site of the initial superoxide production (proposed to be mtNOS) in the first few hours following irradiation (the 'early process'); 2) Identify the mitochondrial sites damaged by ROS/RNS (proposed to be complex III) resulting in further (chronic) superoxide generation (the 'later process') and devise strategies for deactivating these centers; 3) Determine the relative importance of peroxynitrite and hydrogen peroxide production in post-irradiation damage to the electron-transport chain (ETC). Within the framework of these specific aims, it is proposed to develop and test putative drugs designed to prevent the formation of key ROS/RNS at the mitochondrial sites identified as responsible for their generation. In addition to efficacy, the possible toxicity of these compounds (at the level of the ETC) will be evaluated to facilitate improvements in the characteristics of further candidate drugs produced subsequently in iterative rounds of synthesis and testing.