PA-12-149: Research Supplements to Promote Diversity in Health-Related Research (Admin Supp): Metabolomic biomarkers and instrumentation for assessment of radiation injury,

PA-12-149：促进健康相关研究多样性的研究补充（管理补充）：用于评估辐射损伤的代谢组生物标志物和仪器，

• 批准号: 8991790
• 负责人: Albert J Fornace
• 金额: $ 6.02万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-24 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991790
• 关键词: Age; Algorithms; Animal Model; Bioinformatics; Biological Markers; Blood; Burn Trauma; Cells; Clinical; Collection; Data; Data Set; Databases; Detection; Development; Disease; Dose; Dose-Limiting; Exposure to; Filtration; Funding; Gender; Goals; Health; House mice; Housing; Human; Human Volunteers; In Vitro; Inflammatory; Inflammatory Response; Injury; Ionizing radiation; Ions; Laboratories; Lipopolysaccharides; Liquid Chromatography; Lung; Mass Spectrum Analysis; Measures; Metabolic; Methods; Modeling; Monitor; Mus; National Institute of Allergy and Infectious Disease; Neutrons; Organ; Outcome; Paper; Patients; Preparation; Process; Protocols documentation; Publications; Publishing; Radiation; Radiation Injuries; Radiation Toxicity; Reporting; Research; Sampling; Seminal; Sepsis; Series; Serum; Severities; Signal Transduction; Small Intestines; Specificity; Spectrometry; Stress; System; Text; Time; Toxic effect; Urine; Validation; Whole-Body Irradiation; base; biological adaptation to stress; biomarker development; biomarker discovery; biomarker panel; cohort; cost effective; experience; exposed human population; in vivo; insight; instrument; instrumentation; interest; ionization technique; irradiation; liquid chromatography mass spectrometry; member; metabolomics; mouse model; nonhuman primate; novel; radiation response; response; small molecule; stressor

DESCRIPTION (provided by applicant): This proposal combines our metabolomics and radiation-signaling expertise with the expertise of team members in instrumentation for rapid and cost-effective assessment of select metabolites. The overall goals are to develop a reliable database of radiation metabolomic biomarkers in humans from easily-accessible biofluids, and then to refine subset(s) that will allow assessment of select biomarkers with instrumentation that could provide the basis for application in clinical and potentially in-field scenarios. The propose study builds on an extensive track record of accomplishments in radiation metabolomics, as well as the use of approaches, particularly differential mobility spectrometry (DMS), that allows for high-throughput assessment of metabolite biomarkers of interest. In the case of radiation metabolomics, our laboratory and its collaborators have made major contributions in establishing this field using a modern liquid chromatography (LC) mass spectrometry (MS) approach in a variety of animal models as well as in human cells. We have shown in publications over the last several years that they are dose-dependent and timecourse-dependent responses in urine metabolomics profiles after doses of ionizing radiation (IR) that are a NIAID priority. Recently, we have shown that there is evidence for specificity in the IR response in vivo compared to another relevant stressor, which mimics the inflammatory response to sepsis. Our team has also published extensively on the development and refinement of DMS, which should allow for selective "tuning" for metabolite biomarkers without cumbersome LC. We have demonstrated that DMS allows isolation of select metabolites so that they can then be detected with a simplified and miniature MS system. In the case of human biomarker development, we have a collection of biofluids from a large number of patients undergoing total body irradiation (TBI) and have already demonstrated significant metabolomic responses in urine after TBI. Aim 1 will be to develop a robust metabolomic biomarker database for human exposure using our high-end laboratory LCMS approach. Since dose and timecourse sampling is limited in TBI patients, we will use our extensive on-going mouse model datasets, which are funded by a different mechanism, as well as non-human primate samples provided by collaborators to model a much wider range of exposures. In the case of radiation toxicity, we have exciting preliminary data demonstrating that toxicity and lethality, which occurs approximately 2 wk after irradiation, can be distinguished as early as 1 day after irradiation in mice. Aim 2 will develop biomarker panels to distinguish IR biomarker signatures from other injury and disease processes. A modern bioinformatics pipeline, which includes novel in-house algorithms, has been developed to facilitate biomarker discovery. Having developed a robust IR dataset, we will then focus in aim 3 on development of convenient and cost-effective instrumentation that can provide the basis for use in clinical and ultimately in-field scenarios, and refine subsets of IR biomarkers that can be effectively measured with our approaches such as DMS-MS.

描述（由申请人提供）：该提案将我们的代谢组学和辐射信号的专业知识与团队成员的仪器专业知识相结合，以快速且具有成本效益的精选代谢物评估。总体目标是开发一个可靠的数据库，这些数据库是从易于访问的生物流体中的人类中人类中人类中的可靠数据库，然后才能完善子集，该子集将允许评估具有仪器的精选生物标志物，从而为临床和潜在的现场场景提供基础。提出的研究基于广泛的辐射代谢组学成就的记录，以及方法的使用，尤其是差异迁移率光谱法（DMS），允许对感兴趣的代谢物生物标志物进行高通量评估。就辐射代谢组学而言，我们的实验室及其合作者在多种动物模型以及人类细胞中使用现代液相色谱（LC）质谱法（MS）方法做出了重要贡献。在过去的几年中，我们在出版物中表明，它们是剂量依赖性和时代依赖性的反应，这是尿液代谢组学特征的电离辐射剂量（IR），这是NIAID优先级。最近，我们已经证明，与另一个相关的压力源相比，体内IR反应的特异性有证据，该胁迫模仿了对败血症的炎症反应。我们的团队还广泛地发表了有关DMS的开发和完善，这应该允许在没有麻烦的LC的代谢物生物标志物中选择性“调整”。我们已经证明了DMS允许隔离精选代谢物，因此可以通过简化和微型MS系统检测到它们。就人类生物标志物的发展而言，我们收集了来自大量接受全身辐射的患者（TBI）的生物流体，并且在TBI后尿液中已经显示出明显的代谢组反应。 AIM 1将是使用我们的高端实验室LCMS方法开发可靠的代谢组生物标志物数据库，用于人类接触。由于TBI患者的剂量和时间采样受到限制，因此我们将使用我们广泛的持续的小鼠模型数据集，这些数据集由不同的机制资助，以及合作者提供的非人类灵长类动物样本来建模更广泛的暴露范围。在辐射毒性的情况下，我们有令人兴奋的初步数据，表明辐照后约2周发生的毒性和致死性可以在辐照小鼠后1天之前进行区分。 AIM 2将开发生物标志物面板，以将IR生物标志物特征与其他损伤和疾病过程区分开。已经开发出一种现代的生物信息学管道，其中包括新型内部算法，以促进生物标志物的发现。在开发了强大的IR数据集之后，我们将专注于AIM 3上，开发方便且具有成本效益的仪器，可以为临床和最终的现场场景提供基础，并完善可以通过我们的DMS-MS等方法来有效测量的IR生物标志物的子集。