A Molecular Signature of Radiation Injury

辐射损伤的分子特征

• 批准号: 8013116
• 负责人: JOSEPH R NEVINS
• 金额: $ 22.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013116
• 关键词: Affect; Algorithms; Animals; Anterior; Award; Biological; Biological Assay; Blood; Blood Tests; Breast; Cell Line; Cells; Centers of Research Excellence; Chromosome abnormality; Cities; Clinical; Computing Methodologies; Development; Devices; Diagnosis; Diagnostic tests; Disasters; Dose; Event; Exposure to; Gene Expression; Gene Targeting; Genes; Genetic; Gold; Guidelines; Health Personnel; Healthcare; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Individual; Injury; Ionizing radiation; Life; Limb structure; Local Government; Malignant Neoplasms; Maps; Measurement; Mediating; Medical; Medical Societies; Methodology; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Mus; Nuclear; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Radiation; Radiation Injuries; Regression Analysis; Screening procedure; Signal Pathway; Stem cell transplant; Systems Biology; Test Result; Testing; Therapeutic; Time; Translating; Translations; Triage; Whole-Body Irradiation; analytical method; authority; base; body system; cell growth; computerized tools; drug candidate; genome wide association study; genome-wide; genome-wide analysis; improved; in vitro Assay; inhibitor/antagonist; irradiation; knowledge base; malignant breast neoplasm; metagenesis; novel; peripheral blood; research and development; response; therapeutic development

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.

在人口密集的城市发生放射性或核灾难时，成千上万的人可能受到危及生命的电离辐射。对受影响的个人进行快速分类对于有效应对此类事件的卫生保健至关重要。不幸的是，没有一个准确和实用的测试来确定一个人所接受的辐射暴露水平。临床测量是非特异性的，染色体畸变的精细测定需要几天才能完成。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照射个体的辐射状态和剂量水平。随后，我们成功地开发了辐射损伤的PB特征，可以预测小鼠的辐射状态和辐射剂量水平，准确率为96%。与此同时，我们证明了从接受全身照射的患者中开发的人体辐射暴露的PB特征在预测健康人、未照射患者和照射患者的辐射状态方面的准确率为97%。然而，全身照射的PB特征是否可以区分接受异质辐射照射的个体，这在大规模伤亡事件中可能是众多的群体，还有待观察。我们也没有探索辐射改变的途径的生物学意义;这些途径可以为开发减轻辐射损伤的治疗方法提供关键基础。我们将：1）确定部分身体照射的PB特征是否可以被开发为与全身照射的PB特征不同，2）应用高通量计算方法来鉴定在造血细胞中响应于辐射损伤而改变的基因靶标和途径，以及3）在经验证的实验中，测试调节辐射改变的途径的可用药物，作为造血系统辐射损伤的候选缓解剂。辐射模型我们的广泛目标是改进辐射损伤的PB特征，以涵盖具有异质性暴露的那些，并鉴定对辐射损伤有反应的造血细胞中的信号传导途径，作为开发途径特异性药物作为辐射损伤缓解剂的手段。