A molecular signature of radiation injury

如果由于恐怖袭击而发生涉及辐射暴露的大规模伤亡情况，潜在受害者的康复和结果将在很大程度上取决于医疗界的快速和有效反应。由于辐射的影响取决于时间、距离和对放射源震中的屏蔽，可以预见，受影响人群的辐射水平将从严重不显著(例如0-50cGy)到骨髓和免疫抑制(100-400cGy)，再到潜在的生命威胁(&gt；400cGy)。因此，在这种情况下，对于医疗护理人员来说，有效地对哪些人接受了医学上确定的剂量进行分类将是至关重要的。不幸的是，在许多情况下，外部剂量学估计不能准确地预测个人所遭受的生物暴露。辐射暴露的临床征兆，例如 恶心和呕吐是非特异性的，可能存在于大量未受影响的个体中，继发于心理应激。淋巴细胞耗竭动力学还需要在一段时间内采集几次血液以提供预测性剂量学信息。黄金标准，细胞遗传学分析，也需要几天的时间来完成，在此期间可能会失去宝贵的治疗机会。在这项提案中，我们的目标是应用强大的分子 开发一种生物剂量测定测试，该测试可以预测不同水平的辐射暴露，具有高度的敏感性和特异性。首先，我们将建立正常、低剂量、中剂量和高剂量照射小鼠的基因表达谱。然后，我们将根据接受脑外伤的人类患者的分子特征来验证这些签名。接下来，我们将针对从以下地点收集的未知样本来前瞻性地验证签名 以盲目的方式照射小鼠和人类。最后，我们将把这一经过验证的分子图谱转化为可部署的生物剂量学仪器，可用于准确地对潜在的辐射受害者进行分类。

In the event of a mass casualty scenario involving radiation exposure due to a terrorist attack, the recovery and outcome of potential victims will depend heavily on the rapid and efficient response of the medical community. Since the effects of radiation are dependent upon time, distance, and shielding from the epicenter of a radiation blast/source, it can be anticipated that exposure levels across an affected population will range from acutely non-significant (e.g. 0-50 cGy), to myelo- and immunosuppressive (100-400 cGy), to potentially life threatening (> 400 cGy). It will be critical, therefore, in such an event, for the medical caregivers to effectively triage which individuals have received a medically deterministic dose versus the "worried well." Unfortunately, in many instances, external dosimetry estimates will not accurately predict the biological exposure that an individual has sustained. Clinical signs of radiation exposure, such as nausea and vomiting, are non specific and could be present in a large number of unaffected individuals secondary to psychogenic stress. Lymphocyte depletion kinetics also require several blood collections over tim e to provide predictive dosimetry information. The gold standard, cytogenetics analysis, also requires several days to complete, during which time valuable therapeutic opportunities may be lost. In this proposal we aim to apply powerful molecular profiling technology to develop a biodosimetry test that can predict different levels of radiation exposure with a high level of sensitivity and specificity. First, we will develop gene expression profiles of normal, low dose-, intermediate dose-, and high dose-irradiated mice. We will then validate those signatures against the molecular profiles of human patients undergoing TBI. Next we will prospectively validate the signatures against unknown samples collected from irradiated mice and humans in a blinded manner. Finally, we will translate this validated molecular profile into a deployable biodosimetric instrument that can be utilized to accurately triage potential radiation victims.