Universiity of Rochester Center for Medical Countermeasures against Radiation

描述(由申请人提供)：罗切斯特大学CMCR的重点是药物开发，特别是针对四个主要和关键器官和组织的特定晚期终点的研究药物：肺(项目1)、脑(项目2)、皮肤(项目3)和骨髓(项目4)。事实上，拟议中心的组成所固有的是项目之间高度的协同作用，这对于中心在系统性损害情况下开发缓解剂的目标至关重要，因为这将允许项目之间的组织交流，以便分析和关联数据。为此，每个项目都将在适当的情况下使用相同的动物品系、相同的辐射传递方案和相同的药物剂量方案。每个项目都包含体外照射(TBI)和污染、复合损伤(并发或顺序)的模型，并将评估成年动物和新生动物的不同反应，后者作为儿科种群的替代品。此外，我们还提供了CMCR“独特设施”，这是我们在上一次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，还将通过核心C、成像和组织病理学进行标准化的图像分析和组织学准备。因此，每个项目的次要目标将是评估其他项目正在开发的制剂的有效性以及它们自己感兴趣的组织中可能出现的毒理学后遗症。这些次级分析的大部分将通过核心D--药物转化和开发--的统计部分进行。我们的药物核心将监督以下药物的开发： Hompera(R)：P物质的类似物，参与多种炎症性疾病的病理生理学。其中两个项目，1(肺)和4(骨髓)，将分别评估Hompera的晚期终点、肺纤维化和晚期造血功能障碍。 米诺环素：一种耐受性良好且安全的抗生素和消炎药，很容易通过血脑屏障。项目2将评估米诺环素对其终点--辐射诱导的神经炎症--的影响。 IL-12：IL-12不仅通过核苷酸切除修复触发DNA修复，还可能在电离辐射引起的主要损伤即双链断裂的修复中发挥作用。项目3将进一步评估IL-12在辐射和复合损伤模型中的有效性。 Eukarion系列：EUK-189和EUK-207在各种体内辐射损伤模型中具有缓解活性。项目1、2和4将评估EUK-207在各自终点的有效性；项目3将评估EUK-189的局部配方的有效性。 四氢姜黄素：项目3将利用四氢姜黄素的抗炎和清除自由基的特性；这种药物将局部使用。 SecinH3可以稳定血管内皮细胞，抑制细胞因子和生长因子诱导的病理性血管生成和血管渗漏。SecinH3将在项目1和2中进行测试。

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.