Development of a minimally invasive biomarker assay to detect delayed radiation injury

开发微创生物标志物检测来检测迟发性辐射损伤

• 批准号: 10546448
• 负责人: Marjan Boerma
• 金额: $ 45.35万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10546448
• 关键词: Acute; Adult; Algorithmic Software; Algorithms; Animal Model; Bioinformatics; Biological Assay; Biological Markers; Biometry; Brain; Clinical; Clinical Management; Collaborations; Data; Decision Analysis; Development; Early Diagnosis; Early identification; Exposure to; Female; Foundations; Future; Gamma Rays; General Population; Genetic; Guidelines; Heart; High-LET Radiation; Inbreeding; Individual; Injury; Injury to Kidney; Interdisciplinary Study; Ionizing radiation; Kidney; Late Effects; Leg; Linear Energy Transfer; Low Dose Radiation; Lung; Mass Spectrum Analysis; Metabolic; Modeling; Neutrons; Nuclear Warfare; Organ; Outcome; Plasma; Practice Guidelines; Predictive Value; Predisposition; Procedures; Radiation; Radiation Accidents; Radiation Injuries; Radiation exposure; Radiobiology; Rattus; Research Design; Resolution; Risk; Risk Assessment; Roentgen Rays; Sampling; Science; Source; Specificity; Sprague-Dawley Rats; Symptoms; Terrorism; Testing; Time; Tissues; United States Food and Drug Administration; Urine; Validation; Water; Whole-Body Irradiation; Work; biomarker development; biomarker identification; biomarker panel; biomarker validation; biosignature; body system; circulating biomarkers; classification algorithm; clinical care; clinical diagnosis; clinical translation; cohort; diagnostic platform; good laboratory practice; improved; in vivo; indexing; irradiation; lipidomics; male; metabolomics; minimally invasive; multiple reaction monitoring; nonhuman primate; novel; organ growth; organ injury; prediction algorithm; predictive marker; predictive panel; predictive test; prototype; radiation risk; sex; software development; stable isotope; tissue injury; validation studies

PROJECT SUMMARY/ABSTRACT Although the general population continues to be at risk of exposure to ionizing radiation because of nuclear warfare, terrorism, or radiological accidents, there are currently no biomarker assays that are predictive of radiation-induced late injury in specific organs. In cases of heterogeneous exposures and for victims who survive the acute effects, there will be a latent period of months to decades before serious symptoms manifest. This proposal brings together an inter-disciplinary research team with expertise in radiation biology, animal models of tissue injury, biomarker development, biostatistics and bioinformatics to identify analytically validated rapid and minimally invasive assays that predict delayed radiation injury in different organ systems. Discovery and validation of radiation biomarkers are based on the underlying premises that: 1) a signature of radiation exposure is present in biofluids (plasma and urine) at some point prior to clinical diagnosis; and 2) early diagnosis can result in improved clinical care and outcome. Using a discovery-validation study design, we propose to identify metabolic biomarkers of radiation injury to three major organs at risk for delayed complications: kidney, heart and brain (Specific Aim 1), and develop a kit-based assay along with a biomarker scoring algorithm for assessing and predicting injury in these organs (Specific Aim 2). We will make use of our established rat models of partial and total body irradiation to identify plasma and urine biomarkers that predict the extent of injury in the kidney, heart and brain before clinical symptoms appear. For this purpose, we will make use of male and female rats of an inbred and an outbred strain and expose rats to X-rays and a mixed neutron/γ-ray beam. We will determine which matrix (plasma or urine) provides the best predictor for each of the organ systems. We will validate rat biomarker panels in independent cohorts of rats and in banked samples of non-human primates exposed to radiation. Biomarker panels will then be used to develop a prototype metabolite kit in 96-well format and test its technical feasibility in accordance with good laboratory practice guidelines. This prototype kit is required for the rapid future development of a field-deployable minimally invasive biomarker assay that will identify individuals at risk. At the conclusion of these studies, we expect to delineate minimally invasive, high specificity classification algorithms for predicting delayed radiation injuries in kidney, heart and brain with >90% specificity, sensitivity, and positive predictive value. While here we focus on radiation late effects, the standard operating procedures, assay parameters and decision analysis software developed in this study will serve as a foundation for broader based implementation of minimally invasive biomarkers in radiation risk assessment.

项目总结/摘要 虽然由于核武器的存在，一般民众继续面临电离辐射的风险， 战争、恐怖主义或放射性事故，目前还没有生物标志物测定可预测 辐射引起的特定器官的晚期损伤。在不同暴露的情况下， 在急性反应后，会有数月至数十年的潜伏期，然后才会出现严重的病征。 这项建议汇集了一个跨学科的研究团队，在辐射生物学，动物， 组织损伤模型、生物标志物开发、生物统计学和生物信息学， 预测不同器官系统中的延迟辐射损伤的快速和微创检测。发现 辐射生物标志物的验证基于以下基本前提：1）辐射的特征 在临床诊断之前的某个时间点，暴露存在于生物流体（血浆和尿液）中;以及2）早期 诊断可以改善临床护理和结果。使用发现-验证研究设计，我们 建议确定三个主要器官辐射损伤的代谢生物标志物， 并发症：肾脏、心脏和大脑（具体目标1），并开发一种基于试剂盒的检测方法，沿着生物标志物 用于评估和预测这些器官损伤的评分算法（特定目标2）。我们将利用我们的 建立了部分和全身照射的大鼠模型，以鉴定预测 在临床症状出现之前，肾脏、心脏和大脑的损伤程度。为此，我们将 使用近交系和远交系的雄性和雌性大鼠，并将大鼠暴露于X射线和混合的 中子/γ射线束我们将确定哪种基质（血浆或尿液）为每种疾病提供最佳预测因子。 器官系统。我们将在独立的大鼠队列和库存样品中验证大鼠生物标志物组 暴露在辐射下的非人类灵长类动物。生物标志物面板将用于开发原型 代谢物试剂盒，96孔格式，并根据良好实验室规范测试其技术可行性 指南这种原型工具包是快速的未来发展所需要的外地部署的最低限度 侵入性生物标志物检测将识别处于风险中的个体。在这些研究结束时，我们希望 描述预测迟发性放射损伤的微创、高特异性分类算法， 肾、心脏和脑的特异性、敏感性和阳性预测值>90%。在这里，我们将重点放在 辐射迟发效应、标准操作规程、测定参数和决策分析软件 本研究中开发的技术将作为更广泛实施微创手术的基础。 辐射风险评估中的生物标志物。