Rapid Non-invasive Radiation Biodosimetry through Metabolomics

项目3的重点是开发过去在生物体液中辐射暴露的代谢组学特征。 比如尿液和血清。这些生物标记物特别有用，因为它有可能是非侵入性的 样品采集和长时间代谢信号--暴露后数天或数周。代谢组学 到目前为止，开发的信号既可以预测剂量，也可以预测晚期的健康结果。这里的主题是 《超越简单暴露》、《超越剂量》、《超越模型系统》和《优化生物标记物集成》， 这是由各种不同的暴露场景和对策需求所驱动的。 除了简单的曝光：虽然大多数辐射生物剂量学研究都涉及到中间的光子 剂量率，个人在IND后将暴露于的现实暴露情景可能包括：混合 中子+光子照射、非常高的剂量率、可变的低剂量率和局部身体照射。这 CMCR使用独特的辐射设备来模拟这些曝光，这些设备将被用于 评估参考代谢组特征是否可以重建剂量--或者是否需要额外的代谢物 以确定不同的暴露场景。 超越剂量：代谢组生物标记物不仅用于重建过去的辐射剂量，而且 也用于预测光子导致的肺死亡。在这里，我们将评估这些预测能力 在混合的中子+光子曝光之后。从机制上讲，重点将放在辐射诱导的衰老上。 细胞信号转导，这可能在晚期肺损伤的发生发展中起作用。辐射的贡献- 在光子和混合中子+光子诱导的晚期肺中，诱导衰老细胞信号将被评估 损伤，以及它如何影响这些损伤的预测性特征。 超越模型系统：由于大多数生物剂量学研究都必须在动物模型中进行，因此 主题解决了动物和人类辐射暴露的代谢生物标记物之间的联系。 虽然许多相关的暴露不能在人体内直接调查，但来自光子暴露的样本 脑外伤患者可以帮助指导动物模型中的生物剂量测定方法的转换。一个非常大的 来自脑外伤患者、小鼠和NHP的代谢组学数据库将被分析，以检验存在以下假设 这三个物种都有一个共同的辐射反应代谢组学特征。 优化生物标记物集成：CMCR项目中的三个不同的生物标记物系统 细胞遗传学、基因表达和代谢组学反映了能力的不同平衡 吞吐量、产生结果的时间、剂量重建、暴露情景识别和辐射敏感性预测。 我们的共同目标是在各种不同的大规模暴露中确定它们的最佳综合使用 场景。当该项目产生结果时，它们将被用作优化决策树的输入，以 确定哪种化验或化验组合在每个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.