A Molecular Signature of Radiation Injury

在人口稠密的城市发生的辐射或核灾难中，数万人可能会暴露在危及生命的电离辐射水平下。对受影响的个人进行快速分诊对于有效应对此类事件至关重要。不幸的是，没有一种准确和实用的测试来确定一个人所受到的辐射暴露水平。临床测量是非特异性的，染色体异常的精细分析需要几天时间才能完成。我们假设，全基因组分析外周血(PB)中的表达变化可以预测受辐射个体的辐射状态和不同的剂量水平。随后，我们成功地开发出辐射损伤的PB信号，可以预测小鼠的辐射状态和辐射剂量水平，准确率为96%。同时，我们证明了从接受全身照射的患者身上产生的人体辐射暴露的PB信号在预测健康人、未受辐射患者和受辐射患者的辐射状态方面的准确率为97%。然而，全身照射的PB信号是否能区分接受异质辐射照射的个体，这一群体在大规模伤亡事件中可能会很多，仍有待观察。我们也没有探索辐射改变途径的生物学意义；这些途径可以为放射损伤治疗的发展提供关键的基础。我们将：1)确定局部照射的PB信号是否可以与全身照射的PB信号不同，2)应用高通量计算方法来识别在辐射损伤时在造血细胞中改变的基因靶点和通路，以及3)在验证的辐射模型中测试可用于调节辐射改变的通路的现有药物作为辐射损伤对造血系统的候选缓释剂。我们的广泛目标是提炼辐射损伤的PB信号，以涵盖那些异质暴露的人，并识别造血细胞中对辐射损伤有反应的信号通路，以此作为开发途径特异性药物作为辐射损伤缓释剂的手段。

In a radiological or nuclear disaster in a populated city, tens of thousands of people could be exposed to life threatening levels of ionizing radiation. Rapid triage of affected individuals will be essential for an effective health care response to such an event. Unfortunately, there is no single accurate and pracfical test available to determine the level of radiation exposure that a person has received. Clinical measurements are non specific and refined assays for chromosomal aberrations require several days for complefion. We hypothesized that genome-wide analysis of expression changes in the peripheral blood (PB) could predict radiation status and disfinguish dose levels In irradiated Individuals. Subsequently, we succeeded in developing PB signatures of radiation injury that could predict the radiation status and radiation dose level in mice with 96% accuracy. In parallel, we demonstrated that a PB signature of human radiation exposure developed from patients undergoing total body irradiafion was 97% accurate at predicting the radiation status of healthy people, non-irradiated patients and irradiated patients. However, it remains to be seen whether PB signatures of total body irradiation can distinguish individuals who receive heterogeneous radiation exposure, a group that could be numerous in a mass casualty event. We also have not explored the biological significance of the pathways altered by radiation; such pathways could provide the key basis for the development of therapeutics to mifigate radiafion injury. We will: 1) Determine if PB signatures of partial body irradiation can be developed as distinct from PB signatures of total body irradiation, 2) Apply high throughput computational methods to identify gene targets and pathways that are altered in hematopoietic cells in response to radiation injury and 3) Test available drugs which modulate pathways altered by radiation as candidate mitigators of radiation injury to the hematopoietic system in a validated radiation model. Our broad objective is to refine the PB signature of radiation injury to encompass those with a heterogeneous exposure and to identify signaling pathways in hematopoietic cells that are responsive to radiafion injury as a means to develop pathway specific drugs as mitigators of radiation injury.