Radiation Biodosimetry using Gene Expression Signatures

使用基因表达特征进行辐射生物剂量测定

• 批准号: 10687080
• 负责人: Sally A. Amundson
• 金额: $ 59.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-31 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687080
• 关键词: Address; Adolescent; Adult; Age; Animals; Architecture; Biological Assay; Biological Markers; Biological Models; Biostatistics Core; Blood; Blood specimen; Cells; Cessation of life; Complex; Coupled; Cytogenetics; Data; Decision Trees; Development; Devices; Disease Progression; Dose; Dose Rate; Event; Experimental Models; Exposure to; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Goals; Human; Individual; Knowledge; Late Effects; Lung; Lung diseases; Measures; Methodology; Modeling; Mus; Neutrons; Nuclear; Nuclear Accidents; Outcome; Performance; Photons; Pulmonary Inflammation; Radiation; Radiation Injuries; Radiation Pneumonitis; Radiation exposure; Testing; Time; Whole-Body Irradiation; aged; assay development; biodosimetry; biomarker identification; exposed human population; genetic signature; improved; in vivo; irradiation; lung injury; metabolomics; minimally invasive; mouse model; nonhuman primate; outcome prediction; predictive signature; radiation effect; reconstruction; response; senescence; survival prediction; transcriptome sequencing; transcriptomics; transgenic suicide gene; urban area

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.

项目2摘要 项目2解决了以下主题中辐射暴露和伤害的转录组签名： 超越简单的暴露：将测试基因表达特征以重建剂量 复杂的暴露情况，这些场景模仿了预计会在实际辐射 /核中遇到的情况 事件，例如在市区的即兴核装置的地面爆炸。在这种情况下， 在初始闪光期间的暴露率非常高，暴露会使暴露量变得复杂，剂量降低 辐射的速度以及中子和部分屏蔽的存在部分由城市确定 建筑学。独特的曝光设施将用于模仿这些现实情况并测试剂量 使用参考转录组签名重建。签名基因将被替换或添加到 改善剂量重建性能和复杂暴露的表征。 超出剂量：为了解决辐射的晚作用，另一个转录组签名是 可以预测光子诱发肺炎后死亡或存活的开发。混合的影响 然而 结果可预测性的转录组签名正在测试混合中子+光子暴露。这 衰老细胞对肺炎发育的贡献和结果预测的表达 还将评估光子或中子+光子暴露后的基因。 除模型系统之外：生物测量法最终旨在与体内的人类暴露量一起使用，但 测定开发通常使用前体辐照的人类血液或体内辐照的小鼠或非 - 人类灵长类动物。因此，知识的主要差距是关于实验结果的应用 人类的模型。直接比较出现在光子和中子的体内和体内暴露 在非人类灵长类动物和小鼠模型中进行 将评估转录组特征。这些研究将包括少年，成人和老鼠，以量化 年龄对剂量重建的可能影响，并测试前体体模型是否反映了年龄特定的 体内看到的差异。还将解决非人类灵长类动物与人类外推的问题，比较结果 从前中子中子辐照的非人类灵长类和人类血液样本来发展和测试交叉 中子暴露后的物种转化方法进行剂量重建。 优化的生物标志物集成：来自所有三个项目的生物测量方法的数据（项目1： 细胞遗传学，项目2：基因表达，项目3：代谢组学）将通过结合进行分析以确定 每种方法的相对优势，并开发决策树以指导应用 现实世界中的生物测量方法。