Centers for Medical Countermeasures Against Radiation

描述（申请人提供）：对全球核战争的担忧，不像过去那么可能，已经被使用放射性武器的恐怖袭击的真实的潜力所取代。世界各地有大量核材料失踪，这些材料有可能进入黑市，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放射性材料非法贩运的增加，这种袭击的威胁有所增加。不幸的是，几乎没有医疗产品可以对抗核攻击或放射性攻击可能造成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，以预防或治疗辐射引起的伤害。我们已经成立了一个名为辐射对策卓越研究中心（RadCCORE）的联盟，共同合作增加可能的代理人，以检测，减轻和治疗那些暴露于确定剂量的辐射的人（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领先科学家聚集在一起，形成了最全面，包容性，机构间和跨学科的辐射医疗对策中心（CMCR）之一。RadCCORE（www.radccore.org）是一个由学术医疗中心组成的网络：杜克大学、北卡罗来纳州大学、维克森林大学和阿肯色州医学大学，将由七个研究项目和五个支持核心组成。这组研究人员的一个主要好处是他们在正常组织损伤、辐射生物学、物理学、培训和教育领域的长期奉献精神和力量。在过去五年中，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，从精确测量照射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于辐射的人开发医疗方法。 项目二： 放射损伤的分子特征 项目负责人：Chute，J 项目2描述（由申请人提供）：在人口密集的城市发生放射性或核灾难时，成千上万的人可能暴露在危及生命的电离辐射水平下。对受影响的个人进行快速分类对于有效应对此类事件的卫生保健至关重要。不幸的是，没有一个准确和实用的测试来确定一个人所接受的辐射暴露水平。临床测量是非特异性的，染色体畸变的精细测定需要几天才能完成。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，我们成功地开发了辐射损伤的PB特征，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中开发的人体辐射暴露的PB签名在预测健康人、未照射患者和照射患者的辐射状态方面的准确率为97%。然而，全身照射的PB特征是否可以区分接受异质辐射照射的个体，这在大规模伤亡事件中可能是众多的群体，还有待观察。我们也没有探索辐射改变的途径的生物学意义;这些途径可以为开发减轻辐射损伤的疗法提供关键基础。我们将：1）确定部分身体照射的PB特征是否可以被开发为与全身照射的PB特征不同，2）应用高通量计算方法来鉴定在造血细胞中响应于辐射损伤而改变的基因靶标和途径，以及3）在经验证的实验中，测试调节辐射改变的途径的可用药物，作为造血系统辐射损伤的候选缓解剂。辐射模型我们的广泛目标是完善辐射损伤的PB特征，以涵盖具有异质性暴露的那些，并鉴定对辐射损伤有反应的造血细胞中的信号传导途径，作为开发途径特异性药物作为辐射损伤缓解剂的手段。 相关性：如果发生恐怖分子介导的放射性或简易核爆炸，成千上万的人可能会受到危及生命的电离辐射。我们根据血液中的遗传特征开发了一种辐射暴露的外周血测试。我们建议通过对部分辐照动物进行测试来改进该测试，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，并将其对血液系统造成的损害降至最低。

DESCRIPTION (provided by applicant): Concerns about global nuclear war, less likely than in the past, have been replaced by the real potential of a terrorist strike using radiological weapons.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.