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: 10090564
• 负责人: Marjan Boerma
• 金额: $ 45.92万
• 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/10090564
• 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; 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; Plasma; Practice Guidelines; Predictive Value; 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; Tissue Model; Tissues; United States Food and Drug Administration; Urine; Validation; Water; Whole-Body Irradiation; Work; base; biomarker development; biomarker panel; body system; care outcomes; circulating biomarkers; classification algorithm; clinical Diagnosis; clinical care; 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 Althooth普通人群继续处于暴露于核电离辐射的风险 战争，恐怖主义或放射学事故，目前尚无预测的生物标志物测定 辐射引起的特定器官的晚期受伤。 在急性效果中生存，这将是严重症状表现出来几十年的潜在时期。 该提案汇集了具有放射生物学专业知识的前学科研究团队，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的延迟辐射损伤。 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）中存在暴露； 诊断可以改善临床护理和结果。 建议将辐射的代谢生物标志物识别为有延迟风险的三个主要器官 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算法（特定目标2）。 已建立的大鼠局部和全身辐射的大鼠模型，以识别预测的血浆和尿液生物标志物 肾脏受伤的程度 利用IND的雄性和雌性大鼠和杂种菌株，并暴露于X射线和混合 中子/γ射线束。 器官系统。 暴露于辐射的非人类灵长类动物。 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性 指南。 侵入性生物标志物测定在这些研究结束时有危险的人。 描述微创，高规格分类算法，用于预测延迟的辐射损伤 肾脏，心脏和大脑具有> 90％的特异性，灵敏度和阳性预测价值。 辐射后期效果，标准操作程序，测定参数和决策分析软件 在这项研究中以服务为基础开发的基础 辐射风险评估中的生物标志物。