Project-002

尽管普通民众因核辐射而继续面临暴露在电离辐射中的危险 战争、恐怖主义或辐射事故，目前还没有生物标志物分析可以预测 特定器官的放射性迟发性损伤。在不同接触的情况下，对于 在急性影响下存活下来，会有几个月到几十年的潜伏期，然后严重的症状才会显现。 这项建议汇集了一个跨学科的研究团队，他们在辐射生物学、动物 组织损伤、生物标记物开发、生物统计学和生物信息学的模型，以识别经分析验证的 预测不同器官系统延迟辐射损伤的快速和微创检测。发现 辐射生物标记物的验证基于以下基本前提：1)辐射的签名 在临床诊断之前的某个时间点暴露在生物液(血浆和尿液)中；2)早期 诊断可以改善临床护理和预后。使用发现-验证研究设计，我们 建议确定辐射损伤对三个主要器官造成延迟风险的代谢生物标志物 并发症：肾脏、心脏和大脑(特定目标1)，并开发基于试剂盒的检测和生物标记物 评估和预测这些器官损伤的评分算法(具体目标2)。我们将利用我们的 建立大鼠局部和全身照射模型，以确定预测血浆和尿液生物标志物 临床症状出现前肾脏、心脏和脑的损伤程度。为此，我们将 利用近交系和近交系的雄性和雌性大鼠，将大鼠暴露在X射线和混合的 中子/γ射线束。我们将确定哪一种基质(血浆或尿液)对每种情况提供最好的预测 器官系统。我们将在独立的大鼠队列和银行样本中验证大鼠生物标志物面板 非人类灵长类动物暴露在辐射中。生物标记物面板随后将用于开发原型 96孔格式的代谢物试剂盒，并根据良好的实验室实践测试其技术可行性 指导方针。这一原型套件是未来快速开发最低限度可现场部署的 侵入性生物标记物分析，将识别处于危险中的个人。在这些研究结束后，我们预计 描述用于预测延迟性放射损伤的微创、高特异性分类算法 肾、心和脑具有90%的特异性、敏感性和阳性预测价值。在这里，我们将重点放在 辐射滞后效应、标准操作程序、分析参数和决策分析软件 这项研究将为更广泛地实施微创技术奠定基础 辐射风险评估中的生物标志物。

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.