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总结 项目 2 涉及以下主题的辐射暴露和损伤的转录组特征： 超越简单的暴露：将测试基因表达特征以重建剂量 模拟实际辐射/核辐射中预期遇到的复杂暴露场景 事件，例如城市地区简易核装置的地面爆炸。在这样的事件中， 由于初始闪光期间的曝光剂量率非常高，曝光会变得复杂，从而减少剂量 沉降率以及中子和部分屏蔽的存在部分取决于城市 建筑学。将使用独特的暴露设施来模拟这些现实场景并测试剂量 使用参考转录组签名进行重建。特征基因将被替换或添加 提高剂量重建性能和复杂暴露的表征。 超越剂量：为了解决辐射的后期影响，另一个转录组学特征已经被提出 开发出可以预测光子诱发肺炎后死亡或生存的方法。混合的影响 然而，中子+光子暴露对这种肺损伤的影响尚不清楚，现在将对其进行表征， 正在测试混合中子+光子暴露的结果预测转录组特征。这 衰老细胞对肺炎发展的贡献以及结果预测的表达 还将评估光子或中子+光子暴露后的基因。 超越模型系统：生物剂量测定最终旨在用于人体体内暴露，但是 检测开发通常使用离体受辐射的人类血液或体内受辐射的小鼠或非 人类灵长类动物。因此，关于实验结果的应用，存在着巨大的知识差距。 人类的模型。直接比较离体和体内对光子和中子的暴露 在非人类灵长类动物和小鼠模型中进行，以及使用剂量重建的准确性 将评估转录组签名。这些研究将包括幼年、成年和老年小鼠，以量化 年龄对剂量重建的可能影响，并测试离体模型是否反映年龄特异性 体内观察到的差异。还将讨论非人类灵长类动物到人类的外推，比较结果 从离体中子辐照的非人类灵长类动物和人类血液样本中开发和测试交叉 中子暴露后剂量重建的物种转换方法。 优化的生物标志物集成：来自所有三个项目的生物剂量测定方法的数据（项目 1： 细胞遗传学、项目 2：基因表达、项目 3：代谢组学）将结合分析以确定 每种方法的相对优势，并开发决策树来指导应用 现实世界中的生物剂量测定方法。