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.
The multiplicity and criticality of the organs being assessed in our Center has relevance to the radiological terrorism scenario since it is likely that the dose distribution will be highly heterogeneous and will result, in many cases, in one organ or tissue appearing to be more adversely affected than others. However, the specific questions and endpoints being addressed by each of the projects within the proposal derive from our central hypothesis that the individual late effects will develop in the context of a systemic injury and will form part of a radiation-induced, multiple organ dysfunction or failure.
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