Radiation Biodosimetry using Gene Expression Signatures

项目2摘要 项目2涉及以下主题的辐射暴露和伤害的转录签名： 除了简单的暴露：将测试基因表达签名以重建剂量 模拟预计将在实际辐射/核事故中遇到的复杂暴露情景 事件，如城市地区简易核装置的地面爆炸。在这种情况下， 在初始闪光过程中，曝光剂量率非常高，减少了剂量，这将使曝光变得复杂 来自尘埃的速率，以及中子和部分屏蔽的存在，部分由城市 建筑。将使用独特的曝光设备来模拟这些现实场景并测试剂量 使用参考转录签名进行重建。签名基因将被替换或添加到 改善剂量重建性能和复杂曝光的特性。 剂量之外：为了解决辐射的后期影响，另一个转录特征是 开发了一种可以预测光子肺炎后死亡或存活的技术。好坏参半的影响 然而，这种肺损伤的中子光子暴露还不是很清楚，现在将用 正在对混合中子光子暴露进行结果预测转录特征测试。这个 衰老细胞在肺炎发病中的作用及预后预测的表达 光子或中子光子暴露后的基因也将被评估。 超越模型系统：生物剂量学最终旨在用于活体人体暴露，但 检测开发通常使用体外照射的人血或体内照射的小鼠或非照射的 人类灵长类动物。因此，在实验结果的应用方面，存在着很大的知识差距 从模特到人类。体外和体内暴露于光子和中子的直接比较将是 在非人灵长类动物和小鼠模型中进行的，以及使用 将对转录签名进行评估。这些研究将包括幼鼠、成年鼠和老年鼠，以量化 年龄对剂量重建的可能影响，并测试体外模型是否反映了年龄特异性 在活体内看到的差异。非人灵长类动物对人类的外推也将被处理，比较结果 从体外中子辐照的非人类灵长类动物和人类血液样本中开发和测试交叉 中子照射后剂量重建的物种转换方法。 优化的生物标志物集成：来自所有三个项目的生物剂量学方法的数据(项目1： 细胞遗传学，项目2：基因表达，项目3：代谢组学)将被联合分析，以确定 每种方法的相对优势，并开发用于指导应用的决策树 真实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.