Development of Novel Radiation Mitigators

有一种明显的威胁，即通过恐怖主义行动使相当大的人口暴露在辐射之下。 目前，只有一种化学物质，氨磷汀，被批准为辐射防护剂，其毒性相当大。 治疗剂量。迫切需要更多这样的化学品来缓解和治疗 辐射损伤。遗传不稳定，包括DNA缺失，与细胞死亡、细胞功能障碍有关 以及长期后果，如出生缺陷，可能还有其他退行性疾病。辐射 导致DNA链断裂，导致遗传不稳定和DNA缺失。我们之前已经表明， 在酵母、人类细胞以及在小鼠体内，电离辐射都可以诱导DNA缺失。在 在之前的预算期间，我们已经开发了一种高产量的酵母检测方法，并使用这种检测方法来 从ASINEX化学文库中搜索减少细胞杀伤率和DNA删除的化学物质。非常 有趣的是，这些化学物质在小鼠身上被证明是有效的辐射缓释剂，当第一剂量是 照射后24小时涂抹。此外，它们还显著降低了辐射诱导的频率 癌症。在目标1中，酵母中的HTS Del试验将用于从文库中筛选进一步的化学物质 以及来自当前辐射缓释剂周围的目标库。在目标2中，我们将调查 来自酵母的命中结果使用哺乳动物重排试验在哺乳动物细胞中进行筛选。在《目标3》中我们 正在提议在这些缓释剂周围合成有针对性的化学库，并选择最有效的 这些库中的缓释剂。我们还建议筛选新的缓释剂。在《目标4》中，我们还将 使用包括功能基因组学分析在内的各种分析方法来表征缓释剂。使用 功能基因组学分析我们将确定基因控制的缓解效果，以获得 化学干预减轻辐射效应的新靶点。如此新奇的机械装置 靶标可以用来筛选潜在地与这些靶标特别相互作用的新化合物 产生了一种更有效的缓释剂。在目标5中，我们将确定新的 我们将在体内获得的化合物。在目标6中，我们建议使用以下方法来表征动物中的缓释剂 将从项目2和项目3获得信息，项目1将与这些项目密切对接。

There is a perceived threat of exposure of a sizable human population to radiation through terrorist action. Currently, there is only one chemical, amifostine, approved as a radioprotector, which is rather toxic at its therapeutic dose. There is an urgent need for more such chemicals for the mitigation and treatment of radiation injury. Genetic instability, including DNA deletions are involved in cell death, cellular dysfunction as well as long-term consequences such as birth defects and maybe other degenerative diseases. Radiation causes DNA strand breaks resulting in genetic instability and DNA deletions. We have previously shown that DNA deletions are inducible by ionizing radiation in yeast, human cells as well as in vivo in mice. In the previous budget period we have developed a high tliroughput assay with yeast and used this assay to search for chemicals that reduce cell killing as well as DNA deletions from the ASINEX chemical library. Very interestingly, these chemicals turned out to be potent radiation mitigators in mice, when the first dose was applied 24 hours after irradiation. In addition, they significantly reduced the frequency of radiation-induced cancer. In aim 1 the HTS DEL assay in yeast will be used to screen for further chemicals from the libraries and from a targeted library around the current radiation mitigators. In aim 2 we will investigate the effects of the hits from the yeast screen in mammalian cells using a mammalian rearrangement assay. In aim 3 we are proposing to synthesize targeted chemical libraries around those mitigators and select the most potent mitigator from those libraries. We also propose to screen for new mitigators. In aim 4 we will also characterize the mitigators using a variety of assays including a functional genomics assay. Using a functional genomics assay we will determine the genetic control of the mitigation effect in order to obtain novel targets for chemical intervention ofthe mitigation ofthe radiation effect. Such novel mechanistic targets can be used to screen for new compounds that specifically interact with such targets potentially yielding an even more potent mitigator. In aim 5 we will determine radiation mitigation effects ofthe new compounds that we will obtain in vivo. In aim 6 we propose to characterize the mitigators in animals using information will be obtained from projects 2 and 3 with which project 1 will closely interface.