Radiation Biodosimetry using Gene Expression Signatures

项目2摘要 项目2涉及辐射照射和辐射损伤的转录组学特征，主题如下： 除了简单的暴露：基因表达特征将被测试用于重建剂量， 模拟实际辐射/核辐射中预期会遇到的复杂暴露情景 爆炸事件，例如在市区发生的简易核装置的地面爆炸。在这种情况下， 在初始闪光期间，由于非常高的曝光剂量率， 率从落尘，和中子的存在和部分屏蔽部分由城市决定 架构将使用独特的暴露设施来模拟这些现实场景并测试剂量 使用参考转录组学签名进行重建。签名基因将被替换或添加到 改进剂量重建性能和复杂曝光特性。 超越剂量：为了解决辐射的晚期效应，另一个转录组学特征已经被发现。 可以预测光子诱发肺炎后的死亡或存活。混合的影响 然而，中子+光子暴露对这种肺损伤的影响尚不清楚，现在将对其进行表征， 对混合中子+光子暴露测试结果预测转录组学特征。的 衰老细胞对肺炎发展的贡献和结果预测因子的表达 还将评估光子或中子+光子暴露后的基因。 Beyond Model Systems：生物剂量测定最终用于人体体内暴露，但 测定开发通常使用离体照射的人血液或体内照射的小鼠或非体内照射的人血液 人类灵长类动物因此，在应用实验结果方面存在着重大的知识差距。 模型到人类。将直接比较离体和体内暴露于光子和中子的情况， 在非人灵长类动物和小鼠模型中进行，以及使用 将评估转录组签名。这些研究将包括幼年、成年和老年小鼠，以量化 年龄对剂量重建的可能影响，并测试离体模型是否反映年龄特异性 在体内观察到的差异。非人灵长类动物到人类的外推也将得到解决，比较结果 从离体中子辐照的非人灵长类动物和人的血液样本，以开发和测试交叉， 中子照射后剂量重建的物种转换方法。 优化的生物标志物整合：所有三个项目（项目1： 细胞遗传学，项目2：基因表达，项目3：代谢组学）将结合分析，以确定 每种方法的相对优势，并制定决策树，以指导应用 真实的世界情况下的生物剂量学方法。

Project 2 Summary Project 2 addresses transcriptomic signatures of radiation exposure and injury in the following themes: Beyond Simple Exposures: Gene expression signatures will be tested for reconstruction of dose in complex exposure scenarios that mimic those expected to be encountered in an actual radiation / nuclear event, such as a ground-burst detonation of an improvised nuclear device in an urban area. In such an event, exposures will be complicated by the very high dose rate of exposure during the initial flash, decreasing dose rate from fallout, and the presence of neutrons and partial shielding determined in part by the urban architecture. Unique exposure facilities will be used to mimic these realistic scenarios and to test dose reconstruction using a reference transcriptomic signature. Signature genes will be replaced or added to improve both dose reconstruction performance and characterization of complex exposures. Beyond Dose: To address the late effects of radiation, another transcriptomic signature has been developed that can predict death or survival following photon-induced pneumonitis. The impact of mixed neutron+photon exposures on such lung injury is not well known, however, and will now be characterized, with the outcome-predictive transcriptomic signature being tested for mixed neutron+photon exposures. The contribution of senescent cells to the development of pneumonitis and the expression of outcome predictive genes after photon or neutron+photon exposures will also be evaluated. Beyond Model Systems: Biodosimetry is ultimately intended for use with in-vivo human exposures, but assay development typically uses either ex-vivo irradiated human blood or in-vivo irradiated mice or non- human primates. A major gap in knowledge thus exists, regarding the application of results from experimental models to humans. Direct comparison of ex-vivo and in-vivo exposures to both photons and neutrons will be conducted in both non-human primate and mouse models, and the accuracy of dose reconstruction using transcriptomic signatures will be assessed. These studies will include juvenile, adult, and old mice, to quantify the possible impact of age on dose reconstruction, and to test if the ex-vivo model reflects age-specific differences seen in vivo. Non-human primate to human extrapolation will also be addressed, comparing results from ex-vivo neutron irradiated non-human primate and human blood samples to develop and test cross- species conversion approaches for dose reconstruction after neutron exposure. Optimized Biomarker Integration: Data from the biodosimetry approaches of all three Projects (Project 1: cytogenetics, Project 2: gene expression, Project 3: metabolomics) will be analyzed in conjunction to determine the relative strengths of each approach, and to develop decision trees for guiding the application of biodosimetry methodologies in real world situations.