Centers for Medical Countermeasures Against Radiation

描述(申请人提供)：与过去相比，对全球核战争的担忧不太可能发生，取而代之的是使用放射性武器进行恐怖袭击的真正可能性。世界各地有大量核材料失踪，这些材料有可能进入黑市，在那里被恐怖分子获取。因此，近年来，随着全球恐怖组织活动的增加和非法贩运放射性材料的增加，这类袭击的威胁有所增加。不幸的是，很少有医疗产品可以对抗核或辐射攻击可能导致的各种急性和长期毒性。因此，需要各种不同的产品和医疗方法来保护和治疗这样的人群。仍然非常需要扩大现有的医疗选择，以预防或治疗辐射损伤。我们已经成立了一个名为辐射对策研究卓越中心(RadCCORE)的联盟，共同合作增加可能的药物，以检测、减轻和治疗那些暴露在确定剂量的辐射中的人(www.radccore.org/)。辐射生物学、健康物理学、干细胞生物学/移植和免疫学领域的顶尖科学家聚集在一起，组成了最全面、最具包容性、跨机构和跨学科的辐射医学对策中心(CMCR)。RadCCORE(www.radccore.org)是一个学术医疗中心网络：杜克大学、北卡罗来纳大学、维克森林大学和阿肯色大学医学科学中心，将由7个研究项目和5个支持核心组成。这组调查人员的一个主要好处是个人在正常组织损伤、辐射生物学、物理学、培训和教育领域的长期奉献和力量。在过去的五年里，它进一步发展成为一个高度协作和互动的调查小组。该网络涉及广泛的研究领域，从精确测量暴露后外部和内部辐射剂量的方法到开发新的治疗产品以防止短期和长期毒性。 相关性：这个多项目计划将为暴露在辐射中的人开发医疗治疗方法。 项目2： 标题：-辐射损伤的分子标记 项目负责人：华盛顿州丘特市 项目2说明(申请人提供)：在人口稠密的城市发生辐射或核灾难时，数万人可能暴露于危及生命的电离辐射水平。对受影响的个人进行快速分诊对于有效应对此类事件至关重要。不幸的是，没有一种准确而实用的测试来确定一个人所受到的辐射暴露水平。临床测量是非特异性的，染色体异常的精细分析需要几天时间才能完成。我们假设，全基因组分析外周血(PB)中的表达变化可以预测辐射状态并区分受辐射个体的剂量水平。随后，我们成功地开发出辐射损伤的PB信号，可以预测小鼠的辐射状态和辐射剂量水平，准确率为96%。同时，我们证明了从接受全身照射的患者身上产生的人体辐射暴露的PB信号在预测健康人、未受辐射患者和受辐射患者的辐射状态方面的准确率为97%。然而，全身照射的PB信号是否能区分接受异质辐射照射的个体，这一群体在大规模伤亡事件中可能会很多，仍有待观察。我们也没有探索辐射改变的途径的生物学意义；这些途径可能为发展治疗以减轻辐射损伤提供关键基础。我们将：1)确定局部照射的PB信号是否可以与全身照射的PB信号不同，2)应用高通量计算方法来识别在辐射损伤时在造血细胞中改变的基因靶点和通路，以及3)在验证的辐射模型中测试可用于调节辐射改变的通路的现有药物作为辐射损伤对造血系统的候选缓释剂。我们的广泛目标是提炼辐射损伤的PB信号，以涵盖那些异质暴露的人，并识别造血细胞中对辐射损伤做出反应的信号通路，以此作为开发途径特异性药物缓解辐射损伤的一种手段。 相关性：如果发生恐怖分子介导的放射性或简易核爆炸，数万人可能暴露在危及生命的电离辐射水平下。我们已经开发了一种基于血液中遗传特征的辐射暴露外周血液检测方法。我们建议通过对部分受辐射的动物进行测试来改进这项测试，我们建议利用测试结果中的遗传信息来开发治疗辐射损伤的药物，并将其对血液系统的损害降至最低。

DESCRIPTION (provided by applicant): Concerns about global nuclear war, less likely than in the past, have been replaced by the real potential of a terrorist strike using radiological weapons. Significant quantities of nuclear material are missing around the world and these materials could possibility enter the black market where they would be acquired by terrorists. Thus, the threat of such attacks has grown in recent years, with the increased activity of global terrorist organizations and a rise in illicit trafficking of radioactive materials. Unfortunately, very few medical products exist to counter the variety of acute and long-term toxicities that can result from nuclear or radiological attacks. Therefore, a variety of different products and medical approaches are needed to protect and treat such a population. There remains a great need to expand the medical options available to prevent or treat radiation-induced injury. We have formed a consortium termed Radiation Countermeasures Centers of Research Excellence (RadCCORE) to collectively and collaboratively increase possible agents to detect, mitigate and treat those people exposed to deterministic doses of radiation (www.radccore.org/). Leading scientists in the area of radiation biology, health physics, stem cell biology/transplantation and immunology have come together to form one of the most comprehensive, inclusive, inter-institutional, and interdisciplinary Center for Medical Countermeasures Against Radiation (CMCR). RadCCORE (www.radccore.org) is a network of academic medical centers: Duke University, University of North Carolina, Wake Forest University and University of Arkansas for Medical Sciences and will consist of seven research projects and five support cores. A major benefit of this group of investigators has been long-term dedication and strength of the individuals in the areas of normal tissue injury, radiation biology, physics, training and education. Over the past five years, it has further evolved into a highly collaborative and interactive group of investigators. This network has addressed broad areas of research, ranging from methods to precisely measure external and internal radiation doses post-exposure to the development of new therapeutic products to prevent short- and long-term toxicities. RELEVANCE: This multi-project program will develop medical treatments for people exposed to radiation. PROJECT 2: Title: - A Molecular Signature of Radiation Injury Project Leader: Chute, J PROJECT 2 DESCRIPTION (provided by applicant): In a radiological or nuclear disaster in a populated city, tens of thousands of people could be exposed to life threatening levels of ionizing radiation. Rapid triage of affected individuals will be essential for an effective health care response to such an event. Unfortunately, there is no single accurate and practical test available to determine the level of radiation exposure that a person has received. Clinical measurements are non specific and refined assays for chromosomal aberrations require several days for completion. We hypothesized that genome-wide analysis of expression changes in the peripheral blood (PB) could predict radiation status and distinguish dose levels In irradiated Individuals. Subsequently, we succeeded in developing PB signatures of radiation injury that could predict the radiation status and radiation dose level in mice with 96% accuracy. In parallel, we demonstrated that a PB signature of human radiation exposure developed from patients undergoing total body irradiation was 97% accurate at predicting the radiation status of healthy people, non-irradiated patients and irradiated patients. However, it remains to be seen whether PB signatures of total body irradiation can distinguish individuals who receive heterogeneous radiation exposure, a group that could be numerous in a mass casualty event. We also have not explored the biological significance of the pathways altered by radiation; such pathways could provide the key basis for the development of therapeutics to mitigate radiation injury. We will: 1) Determine if PB signatures of partial body irradiation can be developed as distinct from PB signatures of total body irradiation, 2) Apply high throughput computational methods to identify gene targets and pathways that are altered in hematopoietic cells in response to radiation injury and 3) Test available drugs which modulate pathways altered by radiation as candidate mitigators of radiation injury to the hematopoietic system in a validated radiation model. Our broad objective is to refine the PB signature of radiation injury to encompass those with a heterogeneous exposure and to identify signaling pathways in hematopoietic cells that are responsive to radiation injury as a means to develop pathway specific drugs as mitigators of radiation injury. RELEVANCE: In the event of a terrorist-mediated radiological or improvised nuclear detonation, tens of thousands of people may be exposed to life threatening levels of ionizing radiation. We have developed a peripheral blood test for radiation exposure based on genetic features in the blood. We propose to improve this test by testing it against partially irradiated animals and we propose to utilize the genetic information within the test results to develop drugs to treat radiation injury and minimize the damage it causes to the blood system.