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.

如果发生恐怖袭击造成的大规模人员伤亡，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有效反应。由于辐射的影响取决于时间、距离和距辐射爆炸/源中心的屏蔽，因此可以预期，受影响人群的暴露水平范围将非常小（例如 0-50 cGy），骨髓和免疫抑制 (100-400 cGy)，可能危及生命 (> 400 cGy)。因此，在这种情况下，医疗护理人员有效地对已接受医学确定性剂量的个人与“担心的人”进行分类至关重要。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体所承受的生物暴露。辐射暴露的临床症状，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，继发于心因性应激。淋巴细胞耗竭动力学还需要随着时间的推移进行多次血液采集以提供预测剂量测定信息。黄金标准，细胞遗传学分析，也需要几天的时间才能完成，在此期间可能会失去宝贵的治疗机会。在本提案中，我们的目标是应用强大的分子 分析技术开发生物剂量测定测试，可以以高灵敏度和特异性预测不同水平的辐射暴露。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 的人类患者的分子特征来验证这些特征。接下来，我们将针对从以下位置收集的未知样本前瞻性地验证签名 以盲法方式照射老鼠和人类。最后，我们将把这个经过验证的分子谱转化为可部署的生物剂量测定仪器，可用于准确地分类潜在的辐射受害者。