Rapid Non-invasive Radiation Biodosimetry through Metabolomics

项目3的重点是开发生物流体中过去辐射照射的代谢组学特征 例如尿液和血清。这些生物标志物特别有用，因为它们具有非侵入性的潜力。 样品采集和长代谢组学信号寿命-暴露后数天或数周。代谢组 迄今为止开发的特征已经预测了剂量和后期健康结果。这里的主题是 “超越简单暴露”、“超越剂量”、“超越模型系统”和“优化生物标志物整合”， 这是由各种不同的暴露情况和对策需要所激发的。 除了简单的曝光：虽然大多数辐射生物剂量学研究涉及光子在中间 剂量率，IND后个体将暴露的实际暴露情景可能包括： 中子+光子照射、极高剂量率、可变低剂量率和部分身体照射。这 CMCR使用独特的辐照设施来模拟这些暴露，这些设施将用于 评估参考代谢组学特征是否可以重建剂量-或者是否需要额外的代谢物 以确定不同的接触情况。 剂量以外：代谢组学生物标志物不仅可用于重建过去的辐射剂量， 也用于预测光子诱导的肺死亡。在这里，将评估这些预测能力 在混合中子+光子暴露之后。从机制上讲，重点将放在辐射诱导的衰老上。 细胞信号，这是一个可能的球员在发展中的晚期肺损伤。辐射的贡献- 诱导的衰老细胞信号传导将在光子与混合中子+光子诱导的晚期肺 伤害，以及它如何影响这些伤害的预测特征。 超越模型系统：由于大多数生物剂量学研究必须在动物模型中进行，因此， 主题涉及动物与人类辐射照射代谢组学生物标志物之间的联系。 虽然许多相关的暴露不能直接在人类中进行研究，但来自光子暴露的样品 TBI患者可以帮助指导动物模型的生物剂量测定法的翻译。一个非常大 将分析来自TBI患者、小鼠和NHP的代谢组学数据库，以检验以下假设： 这是三个物种共同的辐射反应代谢组学特征。 优化的生物标志物整合：该CMCR计划中的三种不同生物标志物系统 细胞遗传学、基因表达和代谢组学反映了不同的能力平衡， 吞吐量、产生结果的时间、剂量重建、照射场景识别和放射敏感性预测。 我们的共同目标是确定它们在各种不同的大规模暴露中的最佳综合使用 场景随着本项目的结果出现，它们将被用作优化决策树的输入， 确定哪种化验或化验组合在每种辐射事件情景中最有效。

Project 3 focuses on the development of metabolomic signatures of past radiation exposure in biofluids such as urine and serum. These biomarkers are particularly useful because of the potential for non invasive sample acquisition and the long metabolomic signal lifetime - days or weeks after exposure. Metabolomic signatures developed to date have been predictive of both dose and late health outcome. The themes here are “Beyond Simple Exposures”, “Beyond Dose”, “Beyond Model Systems” and “Optimized Biomarker Integration”, which are motivated by the variety of different exposure scenarios and countermeasure needs. Beyond Simple Exposures: While most radiation biodosimetry studies have involved photons at intermediate dose rates, realistic exposure scenarios to which individuals will be exposed after an IND may include: mixed neutron+photon exposure, very high dose rates, variable low dose rates, and partial body exposure. This CMCR uses unique irradiation facilities designed to simulate these exposures, and these will be used to assess if a reference metabolomic signature can reconstruct the dose - or if additional metabolites are required to identify different exposure scenarios. Beyond Dose: Metabolomic biomarkers have been useful not only for reconstructing past radiation dose but also for predicting photon-induced pulmonary death. Here these predictive capabilities will be assessed following mixed neutron+photon exposures. Mechanistically, a focus will be on radiation-induced senescent cell signaling, which is a likely player in the development of late pulmonary injury. The contribution of radiation- induced senescent cell signaling will be evaluated in photon vs. mixed neutron+photon induced late lung injuries, and how it affects the predictive signature of these injuries. Beyond Model Systems: In that most biodosimetry studies are of necessity conducted in animal models, this theme addresses the link between metabolomic biomarkers of radiation exposure in animals vs. humans. Although many relevant exposures cannot be directly investigated in humans, samples from photon-exposed TBI patients can help guide the translation of biodosimetry assays from animal models. A very large metabolomic database from TBI patients, mice, and NHPs will be analyzed to test the hypothesis that there is a common radiation-responsive metabolomics signature across all three species. Optimized Biomarker Integration: The three different biomarker systems in this CMCR program cytogenetics, gene expression, and metabolomics reflect different balances of capabilities in terms of throughput, time-to-result, dose reconstruction, exposure scenario identification and radiosensitivity prediction. Our common goal is to identify their optimal integrated usage in a wide variety of different large-scale exposure scenarios. As results emerge from this Project, they will be used as input to optimize decision trees to determine which assay, or combination of assays, will be most effective in each radiation event scenario.