Rapid Non-Invasive Radiation Biodosimetry through Metabolomics

项目总结(见说明)： 最近的恐怖袭击从根本上和永久性地改变了国内安全。随之而来的是这些 清醒地认识到我们没有足够的装备来处理放射性核弹的爆炸 散布装置(RDD或所谓的“脏弹”)或简易核装置(IND)。的发展。 快速、微创的生物剂量测定，可现场部署，足够可靠，可指导 在不同条件下暴露于多种类型电离辐射的人群的卫生保健水平很高 优先考虑。我们的项目解决了这一优先事项，并使用了强大的全局分析功能 代谢组学，一个独特的生物标记物发现平台，特别适合于分析生物流体，如血液和 需要最小限度或非侵入性程序才能获得的尿液。我们已经使用代谢组学来定义 在小鼠和大鼠的尿液辐射反应，并正在利用这些发现来指导在人类身上的发现。我们 建议将我们的研究扩展到更真实的场景，例如(1)低剂量率暴露，(2) 因屏蔽某些器官和组织而导致的部分身体暴露；(3)放射性同位素暴露 在IND或RDD之后，以及(4)中子和低线能量转移(LET)辐射的混合暴露 典型的印第安人。我们也在关注预测预后的生物标志物的发展。 近致命性暴露的个体结果以及涉及生物标记物反应的机制。 我们的研究将使用几种近交系小鼠以及三种转基因小鼠 小鼠品系，所有这些品系对电离辐射都有不同的敏感性。作为比较，人类外围设备 在体外照射后，还将对白细胞样本进行分析。我们的方法是利用 超高性能液体的精致分辨率和精确质量测量能力 已被证明非常有用的色谱-飞行时间质谱学代谢组学平台 到目前为止。我们的代谢组学分析将与转录组分析并行运行(项目2)和 蜂窝终端(项目1)，共享许多相同的样本。我们的目标是为 相关真实世界辐射暴露的微创生物剂量测定，并通过其寻找生物标志物 与辐射有关的最严重的伤害可能会尽早被识别出来。

PROJECT SUMMARY (See instructions): Domestic security was radically and permanently changed by recent terrorist attacks. With these has come the sobering recognition that we are not adequately equipped to handle the detonation of a radiological dispersal device (RDD or so-called "dirty bomb") or improvised nuclear device (IND). The development of rapid, minimally invasive biodosimetry that is field-deployable and reliable enough to guide decisions for the health care of populations exposed to multiple types of ionizing radiation under various conditions is a high priority. Our project addresses this priority and uses the powerful global profiling capabilities of metabolomics, a biomarker discovery platform uniquely suited for the analysis of biofluids such as blood and urine that require minimally- or non-invasive procedures to acquire. We have used metabolomics to define a urinary radiation response in mice and rats and are using these findings to guide discovery in humans. We propose to expand our research into more real-worid scenarios such as (1) low dose-rate exposures, (2) partial body exposures resulting from shielding of certain organs and tissues, (3) exposures to radioisotopes following an IND or RDD, and (4) mixed exposures to neutrons and low linear energy transfer (LET) radiation typical of an IND. We are also focusing attention on the development of prognostic biomarkers to predict individual outcomes from near lethal exposures as well as the mechanisms involved in biomarker responses. Our studies will be conducted using several inbred strains of mice as well as three genetically modified mouse strains, all of which have varying sensitivities to ionizing radiation. For comparison, human peripheral white blood cell samples will also be analyzed after ex vivo irradiation. Our approach is to harness the exquisite resolution and accurate mass measurement capabilities of the Ultra-Performance Liquid Chromatography-time-of-flight mass spectrometry metabolomics platform that has proven enormously useful to date. Our metabolomics analyses will be run in parallel with transcriptomics analyses (Project 2) and cellular endpoints (Project 1), sharing many of the same samples. Our goals are to define a strategy for minimally invasive biodosimetry for relevant real-worid radiation exposures and to find biomarkers by which the most severe radiation-related injuries may be identified as eariy as possible.