Non-invasive radiation biodosimetry through metabolomics

该项目将把我们的代谢组学和压力信号专业知识与Sionex公司的传感器芯片专业知识结合起来，开发使用代谢标志物对辐射暴露和损伤进行快速非侵入性评估的仪器，从而解决该联盟的总体主题。体内辐射可以触发许多参与细胞间信号传递的基因的表达，这些基因的蛋白质可以对细胞代谢产生广泛的影响。我们来自现代代谢组学方法的初步数据表明，这些变化反映在尿液和痰中代谢物光谱的变化上。这样的代谢分析提供了几个关键的优势，包括简单，非侵入性的收集，因此有可能进行非常高吞吐量的生物剂量计筛选。我们还将调查使用 汗液中的新陈代谢特征，这将进一步增加产量。基础支持研究将包括在小鼠模型系统中进行的表达谱分析和代谢物分析，以确定代谢组学中反映的组织和信号通路 改变。尖端的信息学分析将与信息学核心合作，用于选择完全表征的代谢组学标记，以开发最佳的辐射代谢组学特征。转译研究将使用全身照射患者的样本将这些签名扩展到人类。代谢体辐射生物剂量学实用产品的开发需要产品开发的四个阶段，包括发现、可行性、面包板研究和原型开发；本项目包括所有这些阶段。总之，我们将与Sionex公司、产品开发核心和制造核心合作，在现有最先进技术的基础上开发基于代谢组学的便携式高通量辐射生物剂量计，用于现场部署。随着辐射反应基因表达谱仪器的开发(项目2)，这些谱分析方法是高通量辐射生物剂量测定的补充方法。

This project will combine our metabolomics and stress-signaling expertise with the sensor-chip expertise of Sionex Corporation, to develop instrumentation for rapid non-invasive assessment of radiation exposure and injury using metabolic markers, thus addressing the overall theme of the Consortium. Irradiation in vivo triggers the expression of many genes involved in intercellular signaling, whose proteins can have wide-ranging effects on cellular metabolism. Our preliminary data from a modern metabolomics approach indicate that these changes are reflected in alterations in the spectrum of metabolites in urine and sputum. Such metabolomic analyses offer several key advantages including simple, non-invasive collection, and thus the potential for a very high-throughput biodosimeter screening. We will also investigate the potential for using a metabolomic signature in sweat, which would increase throughput still further. Basic supporting studies will include expression profiling and metabolite analyses carried out in mouse model systems, to determine the tissues and signaling pathways whch are reflected in metabolomics changes. Cutting-edge informatics analyses, in collaboration with the Informatics Core, will be used to select thoroughly characterized metabolomics markers to develop an optimal radiation metabolomics signature. Translational studies will extend these signatures into humans using samples from patients having total body irradiation. Development of a practical product for metabolomic radiation biodosimetry requires four phases of product development, encompassing discovery, feasibility, breadboard research, and prototype development; this project encompasses all of these. In summary, in concert with Sionex Corporation, the Product Development Core, and the Fabrication Core, we will build on existing state-of-the-art technology to develop a metabolomics-based portable high-throughput radiation biodosimeter, for deployment in the field. Together with the development of instrumentation for gene expression profiling of radiation response (Project 2), these profiling approaches represent complementary approaches for high-throughput radiation biodosimetry.