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.

项目摘要/摘要 尽管由于核能，总人口仍然处于暴露于电离辐射的风险 战争，恐怖主义或放射性事故，目前尚无生物标志物测定 辐射引起的特定器官的晚期受伤。如果发生异质暴露和虐待 在急性影响下生存，几十年来，严重的症状表现出来。 该提案汇集了一个跨学科研究团队，具有辐射生物学专业知识，动物 组织损伤，生物标志物发展，生物统计学和生物信息学模型，以识别经分析验证的 快速和最小的侵入性测定，可预测不同器官系统中延迟的辐射损伤。发现 辐射生物标志物的验证是基于：1）辐射签名的基础前提 在临床诊断之前的某个时候，在生物流体（血浆和尿液）中呈现暴露； 2）早 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 提议确定对有延迟风险的三个主要器官的辐射损伤的代谢生物标志物 并发症：肾脏，心脏和大脑（特定目标1），并开发基于套件的测定法和生物标志物 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 已建立的大鼠局部和全身照射模型，以识别预测的血浆和尿液生物标志物 出现临床症状之前，肾脏，心脏和大脑受伤的程度。为此，我们将 利用近交和杂种菌株的雄性和雌性大鼠，将大鼠暴露于X射线和混合 中子/γ射线束。我们将确定哪种矩阵（等离子体或尿液）为每个矩阵提供了最佳的预测指标 器官系统。我们将在独立的大鼠和银行样品中验证大鼠生物标志物面板 暴露于辐射的非人类私人。然后，生物标志物面板将用于开发原型 以96孔格式的代谢物套件，并根据良好的实验室实践测试其技术可行性 指南。该原型套件是最低限度的田野开发的快速开发所必需的 侵入性生物标志物测定法，将识别有风险的人。在这些研究结束时，我们希望 描述微创，高特异性分类算法，用于预测延迟辐射损伤 肾脏，心脏和大脑具有> 90％的特异性，灵敏度和阳性预测价值。在这里，我们专注于 辐射后期效果，标准操作程序，测定参数和决策分析软件 在本研究中开发的将成为基于更广泛的最低侵入性实施的基础 辐射风险评估中的生物标志物。