Metabolomics Based Prediction of Delayed Effects of Acute Radiation Exposure

摘要 由于放射性事故或核恐怖主义而使受害者暴露在电离辐射中会导致急性 辐射综合症。由于一些努力导致了针对这些疾病的医学对策的发展 由于急性辐射中毒，受害者在放射性事件中幸存下来的机会大大增加。 然而，在急性影响中幸存下来的受害者，将有几个月到几十年的潜伏期 延迟性损伤明显。晚期器官损伤逐渐不可逆转，对生活质量产生不利影响，并可能 事实证明这是危及生命的。因此，先发制人地识别有这种后遗症风险的个体在 决策过程是确定时机和选择最合适的干预策略的过程。 基于代谢组学的生物标记物分析在各种疾病的临床翻译中的可信度正在迅速增加 设置。我们的初步研究强烈表明，从高分辨率质量中获得的多分析物轮廓 光谱分析平台提供了稳健和早期的辐射损伤指标，具有很高的翻译价值。在这 第一阶段研究，采用发现-验证性研究设计，我们建议确定预期代谢 辐射损伤的生物标志物有两个主要器官有延迟并发症的风险：心脏和大脑。最初，我们 将利用γ-射线暴露的小鼠模型来识别预测程度的血浆和尿液生物标志物 在临床症状出现之前就会在心脏和大脑中表现出来的损伤。我们不仅会发现新的 生物标志物，但也在独立的小鼠队列中验证它们。我们将确定哪种基质(血浆或 尿液)为每个器官系统提供了最好的预测指标(技术目标1)。随后，我们将 在接触γ的男性和女性NHP的血浆和尿液样本中验证这些生物标志物- 并对器官损伤和生存结果进行长期随访(技术目标2)。FDA的指导方针 关于生物标记物的开发和共同开发，以确保监管方面的考虑 在这一进程的所有步骤中都考虑到这一点。这一研究领域的大多数研究确定尿液或血浆代谢物 当在辐射后96小时内测量时，这将区分受辐射和未受辐射的动物。 虽然这种方法在确定一个人所受的辐射剂量方面有价值，但它不能预测 迟发性辐射损伤的风险。该项目将填补这一空白，并成为首批 识别和验证延迟性辐射损伤的生物标志物面板。圆满完成技术目标 将允许选择生物标志物面板，以便为基于试剂盒的分析验证做好准备 在随后的第二阶段应用中。综上所述，这些研究最终将使 一种商业上可行的基于试剂盒的配对诊断测试，可用于识别有风险的个人 因辐射暴露而出现延迟性损伤。

Abstract Exposure of victims to ionizing radiation due to a radiological accident or nuclear terrorism leads to the acute radiation syndrome. Since several efforts have led to the development of medical countermeasures against these acute radiation toxicities, the chance that victims survive a radiological event has significantly increased. However, in victims who survive the acute effects, there will be a latent period of months to decades before delayed injuries manifest. Late organ injury is progressively irreversible, adversely affects quality of life and may prove life-threatening. Therefore, pre-emptive identification of individuals at risk for such late effects is critical in the decision process to determine the timing and choice of the most appropriate intervention strategies. Metabolomics-based biomarker assays are fast gaining credence for clinical translation in a variety of disease settings. Our preliminary studies strongly suggest that multi-analyte profiles obtained from a high-resolution mass spectrometry platform provide robust and early indicators of radiation injury with high translational value. In this Phase I study, using a discovery-validation study design, we propose to identify anticipatory metabolic biomarkers of radiation injury to two major organs at risk for delayed complications: heart and brain. Initially, we will make use of murine models of γ-ray exposure to identify plasma and urine biomarkers that predict the extent of injury that will manifest in the heart and brain before clinical symptoms appear. We will not only discover new biomarkers, but also validate them in independent cohorts of mice. We will determine which matrix (plasma or urine) provides the best predictor for each of the organ systems (Technical Objective 1). Subsequently, we will validate these biomarkers in plasma and urine samples obtained from male and female NHPs exposed to γ- radiation and followed up long term for organ injury and survival outcomes (Technical Objective 2). FDA guidance on biomarker development and co-development will be followed to ensure regulatory considerations are taken into account at all steps in the process. Most studies in this area of research identify urine or plasma metabolites that differentiate between irradiated and unirradiated animals when measured within 96 hours after radiation. While this approach has value in determining which radiation dose one was exposed to, it does not predict someone’s risk for developing delayed radiation injuries. This project will fill this gap and be among the first to identify and validate biomarker panels of delayed radiation injuries. Successful completion of technical objectives will enable the selection of biomarker panels that would be ready for analytical validation for a kit-based assay in a subsequent Phase II application. Taken together, these studies, ultimately, will enable the development of a commercially viable kit based companion diagnostic test that can be used for identifying individuals at risk for developing delayed injuries from radiation exposure.