Universiity of Rochester Center for Medical Countermeasures against Radiation

描述（由申请人提供）：罗彻斯特大学CMCR的重点是药物开发，特别是研究针对四个主要和关键器官和组织的特定晚期终点的药物：肺（项目1），脑（项目2），皮肤（项目3）和骨髓（项目4）。事实上，拟议中心的组成固有的是项目之间的高度协同作用，这对于中心在系统性损伤背景下开发缓解剂的目标至关重要，因为它将允许项目之间的组织交换以进行分析和数据关联。为此，在适当的情况下，每个项目将使用相同的动物品系、相同的辐射输送方案和相同的药物剂量方案。每个项目都包括外照射（TBI）和污染模型，联合损伤（并发或顺序），并将评估成年动物和新生动物的不同反应，后者作为儿科人群的替代。此外，我们还拥有CMCR“独特设施”，这是我们在上一个资助期间开发的内部污染室。除了由个别项目进行的分析外，标准化的图像分析和组织学准备将通过核心C，成像和组织病理学进行。因此，每个项目的第二个目标将是评估其他项目正在开发的药剂在其自身有关组织中的有效性和可能的毒理学后遗症。这种二次分析的大部分将通过核心D，药物翻译和开发的统计组件进行。我们的药物核心将监督以下药物的开发：

DESCRIPTION (provided by applicant): The focus of the University of Rochester CMCR is drug development, in particular investigating agents targeted at specific, late endpoints in four primary and critical organs and tissues: the lung (Project 1), brain (Project 2), skin (Project 3) and bone marrow (Project 4). Indeed, inherent to the composition of the proposed Center is the high degree of synergism between the projects which is critical to the Center's goal of developing mitigating agents in the context of a systemic injury, since it will allow for the interchange of tissues between projects for analysis and correlation of data. To this end, each of the projects will use the same animal strain, the same radiation delivery protocols, and the same drug dose protocols, when appropriate. Each project incorporates models of external irradiation (TBI) and contamination, combined injury (concurrent or sequential), and will assess differential responses in adult and neonate animals, the latter acting as a surrogate for the pediatric population. Moreover, we also have available a CMCR "Unique Facility," our internal contamination chamber developed during the previous funding period. In addition to analyses being carried out by individual projects, standardized image analysis and histological preparation will be performed through Core C, Imaging & Histopathology. Thus, a secondary objective for each of the projects will be the assessment of agents being developed by the other projects in terms of effectiveness and possible toxicological sequelae in their own tissue of interest. Much of this secondary analysis will be performed through the statistical component of Core D, Drug Translation and Development. Our Drug Core will oversee the development of the following agents: Homspera(r): an analogue of Substance P which is involved in the pathophysiology of numerous inflammatory diseases. Two of the Projects, 1 (lung) and 4 (bone marrow), will assess Homspera on their late endpoints, pulmonary fibrosis and late hematopoiesis dysfunction, respectively. Minocycline: a well-tolerated and safe antibiotic and anti-inflammatory that readily crosses the blood-brain barrier. Project 2 will assess the effect of minocycline on its endpoint, radiation-induced neuroinflammation. IL-12: Not only does IL-12 trigger DNA repair through nucleotide excision repair, but it also may play a role in initiating repair of the principal injury induced by ionizing radiation, i.e. double strand breaks. Project 3 will further assess the effectiveness of IL-12 in its radiation and combined injury models. Eukarion Series: EUK-189 and EUK-207 have mitigation activity in various in vivo models for radiation-induced injury. Projects 1, 2, and 4 will assess the effectiveness of EUK-207 on their respective endpoints; Project 3 will assess the effectiveness of a topical formulation of EUK-189. Tetrahydrocurcumin: Project 3 will make use of both the anti-inflammatory and radical scavenging properties of tetrahydrocurcumin; this agent will be administered topically. SecinH3 has been shown to stabilize the endothelium and inhibit pathologic angiogenesis and vascular leak induced by cytokines and growth factors. SecinH3 will be tested in Projects 1 and 2.