Radiation Dose-Dependent Interventions

该辐射医疗对策中心（CMCR）的主要目标是开发剂量测定和医疗产品，以便进行剂量适当的干预，减轻辐射暴露的影响。我们建议整合三种不同的方法剂量学的发展：光学，蛋白质组学和mRNA检测，以创建一个准确的“用户友好”的生物剂量计。将在临床相关犬模型中使用细胞因子和基于细胞的治疗开发剂量适当的干预措施。项目1将使用非侵入性光学成像和光谱学评估暴露皮肤的变化，作为准确测量辐射暴露的手段。项目2将测试辐射诱导的蛋白质组（血浆、外周血淋巴细胞或尿液）变化是否可作为暴露的临床生物标志物。项目3将开发血浆和外周血剂量测定法，利用实时聚合酶链反应（RT/PCR）对辐射诱导的基因表达进行定量。将在暴露于不同剂量全身照射（TBI）的犬中研究补充和综合剂量测定方法，并在接受放射治疗的患者中进行验证。另外三个项目专注于开发基于细胞因子和细胞的疗法。对于暴露于4至7戈瑞（戈伊）TBI的犬，项目4将询问“离体扩增髓系祖细胞的现成冻存通用供体细胞产品是否可以支持粒细胞产生，直到内源性造血系统恢复。对于暴露于7至10戈伊的狗，项目5将使用主要组织相容性复合体（MHC）不匹配的脐带血（UCB）优化供体植入和快速中性粒细胞恢复，其中数千单位已经冷冻保存。项目6将通过开发方法来评估干细胞的替代来源，以提高延迟MHC不匹配成人干细胞移植的安全性和有效性。建议采用三个科学核心：辐射剂量测定、犬资源和细胞治疗来支持所有6个研究/开发项目。一个行政核心将提供科学和预算监督。它还将管理教育和试点项目核心。使用完善的犬模型，其结果可以外推到人类，该CMCR将开发生物剂量测定和基于细胞的疗法，使之有可能为核恐怖袭击的受害者提供剂量适当的干预措施。

The primary goal of this Center for Medical Countermeasures against Radiation (CMCR) is to develop dosimetry and medical products that will allow for dose-appropriate interventions that mitigate the effects of radiation exposure. We propose to integrate three different approaches for dosimetry development: optical, proteomics, and mRNA detection to create an accurate 'user-friendly' biodosimeter. Dose-appropriate interventions will be developed using cytokine and cell-based therapies in the clinically relevant dog model. Project 1 will assess changes in exposed skin using non-invasive optical imaging and spectroscopy as a means to accurately measure radiation exposure. Project 2 will test if radiation induced changes in the proteome (plasma, peripheral blood lymphocytes or urine) can serve as a clinical biomarker of exposure. Project 3 will develop dosimetry assays for plasma and peripheral blood that quantitate radiation induced gene expression using real-time polymerase chain reaction (RT/PCR). The complementary and integrated dosimetry methods will be studied in dogs exposed to varying doses of total body irradiation (TBI) and validated in patients undergoing radiation therapy. Three additional projects focus on the development of cytokine and cell based therapies. For dogs exposed to 4 to 7 Gray (Gy) TBI, Project 4 will ask if an "off the shelf cryopreserved, universal donor cell product of ex vivo expanded myeloid progenitors can support granulocyte production until the endogenous hematopoietic system recovers. For dogs exposed to 7 to 10 Gy, Project 5 will optimize donor engraftment and rapid neutrophil recovery using major histocompatibility complex (MHC)-mismatched umbilical cord blood (UCB), thousands of units of which are already cryopreserved. Project 6 will evaluate an alternative source of stem cells by developing methods to improve the safety and effectiveness of delayed MHC- mismatched adult stem transplantation. Three scientific cores, Radiation Dosimetry, Canine Resource, and Cell Therapy are proposed to support all 6 research/ development projects. An Administrative Core will provide scientific and budgetary oversight. It will also administer both an Educational and Pilot Project Core. Using the well-established canine model, the results from which can be extrapolated to humans, this CMCR will develop biodosimetry and cell based therapies that make it possible to provide dose appropriate interventions to victims of a nuclear terrorist attack.