A molecular signature of radiation injury

辐射损伤的分子特征

• 批准号: 7052918
• 负责人: JOSEPH R NEVINS
• 金额: $ 26.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052918
• 关键词: biomarker; bioterrorism /chemical warfare; clinical research; cooperative study; emergency health services; gene expression profiling; human subject; laboratory mouse; radiation detector; radiation dosage; technology /technique development; whole body irradiation dosage

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.

如果发生涉及恐怖袭击造成辐射照射的大规模伤亡情况，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、距离和对辐射冲击波/辐射源中心的屏蔽，因此可以预计，受影响人群的照射水平将从急性非显著性（例如0-50 cGy）到骨髓和免疫抑制（100-400 cGy）到潜在的生命威胁（> 400 cGy）。因此，在这种情况下，医疗护理人员必须有效地分类哪些人接受了医学上确定的剂量，哪些人接受了“担心的剂量”。“不幸的是，在许多情况下，外部剂量测定估计无法准确预测个人所承受的生物照射。辐射暴露的临床症状，如 恶心和呕吐是非特异性的，并且可能存在于大量继发于心因性应激的未受影响的个体中。淋巴细胞消耗动力学还需要随时间多次采血，以提供预测性剂量测定信息。黄金标准，细胞遗传学分析，也需要几天才能完成，在此期间，宝贵的治疗机会可能会失去。在这项提案中，我们的目标是应用强大的分子 在这方面，我们需要一种分析技术，以开发一种生物剂量测定测试，这种测试能够以高度的灵敏度和特异性预测不同的辐射照射水平。首先，我们将开发正常，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TBI的人类患者的分子谱来验证这些特征。接下来，我们将前瞻性地验证签名对未知样本收集， 以盲法照射小鼠和人类。最后，我们将把这个经过验证的分子谱转化为一个可部署的生物剂量测定仪器，可以用来准确地分类潜在的辐射受害者。