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; 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引起的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学界的快速有效反应。由于辐射的影响取决于时间，距离和与辐射爆炸/来源的中心屏蔽，因此可以预见的是，受影响人群的暴露水平范围从敏锐的不显着（例如0-50 CGY）到骨髓和免疫质量培训（100-400 CGY），到潜在的威胁生活，到威胁生活的生命（> 400 CGY）。因此，在这种情况下，对于医学护理人员来说，有效分类的是，个人已经接受了医学确定性的剂量而不是“担心”。不幸的是，在许多情况下，外部剂量估计不会准确预测一个人所维持的生物学暴露。辐射暴露的临床迹象，例如 恶心和呕吐是非特异性的，并且可能存在于许多继发于心理压力的未受影响的个体中。淋巴细胞耗尽动力学还需要在TIM E上进行几个血液收集，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，在此期间可能会丢失有价值的治疗机会。在此提案中，我们旨在应用强大的分子 分析技术以开发生物测量测试，该测试可以通过高敏感性和特异性来预测不同水平的辐射暴露。首先，我们将开发正常，低剂量，中间剂量和高剂量辐照小鼠的基因表达谱。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，我们将前瞻性地验证签名，以从从中收集的未知样本 以盲目的方式辐照小鼠和人类。最后，我们将将这一经过验证的分子剖面转换为可部署的生物测量仪器，可用于准确分类潜在的辐射受害者。