Rapid Non-Invasive Radiation Biodosimetry through Metabolomics

项目总结（见说明）： 最近的恐怖主义袭击彻底和永久地改变了国内安全。伴随着这些 我们清醒地认识到，我们没有足够的装备来处理核爆炸事件， 扩散装置（RDD或所谓的“脏弹”）或简易核装置（IND）。的发展 快速，微创生物剂量测定，是现场部署和可靠，足以指导决策， 对在各种条件下受到多种类型电离辐射的人群的保健是一个高风险的问题。 要务我们的项目解决了这一优先事项，并使用强大的全球分析功能， 代谢组学是一种生物标志物发现平台，独特地适用于分析生物流体，如血液和 需要微创或非侵入性手术才能获得的尿液。我们使用代谢组学来定义 尿辐射反应的小鼠和大鼠，并利用这些发现来指导人类的发现。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） 由于某些器官和组织受到屏蔽而造成的局部身体照射，（3）放射性同位素照射 IND或RDD后，以及（4）混合暴露于中子和低线性能量转移（LET）辐射 我们还将注意力集中在预后生物标志物的发展上，以预测 近致死暴露的个体结果以及生物标志物反应所涉及的机制。 我们的研究将使用几种近交系小鼠以及三种转基因小鼠进行。 小鼠品系，所有这些品系对电离辐射的敏感性各不相同。相比之下，人类外周 还将在离体辐照后分析白色血细胞样本。我们的方法是利用 超高性能液体的高分辨率和精确的质量测量能力 色谱-飞行时间质谱代谢组学平台已被证明非常有用 迄今我们的代谢组学分析将与转录组学分析（项目2）并行运行， 蜂窝端点（项目1），共享许多相同的样本。我们的目标是制定一项战略， 微创生物剂量测定相关的现实世界的辐射暴露，并找到生物标志物， 最严重的辐射相关损伤可以尽可能早地被识别。

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.