Post-Irradiation Intervention to Mitigate and Treat Non*

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The overall goal of the Center is to develop pharmacologic approaches for the mitigation and treatment of the non-hematological radiation injuries that will occur in victims of radiological terrorism or radiation accidents who receive doses in excess of 5 Gy, and for whom hematological toxicity is prevented or avoided. For uniform total body irradiation, injury to bone marrow is likely to be the primary life-threatening injury. But for partial-body exposure or for internally-deposited radioisotopes (where radiation doses may be high but some bone marrow may be spared), or if the bone marrow damage can be treated with cytokines or stem cell transplants, other types of acute (e.g., Gl, skin, lung) and late (e.g. renal, lung, CNS) injuries are expected to occur. It is these non-hematological injuries which are the focus of the proposed Center; although treatment and mitigation of injuries to these tissues will be of little importance to victims of radiological terrorism or radiation accidents unless there are advancements in the mitigation and treatment of hematological injuries. The Center will be a Consortium made up of 5 projects and 5 cores drawn from 4 institutions: the Medical College of Wisconsin, the Henry Ford Health Systems, the University of Toronto, and Eukarion, Inc. The organ systems to be studied are the Gl tract (Project 1), the kidney (Project 2), the lung (Projects 3 and 4) and the CNS (Project 5), as these are some of the major organ systems that will be at risk if doses exceed 5 Gy and if fatal hematological injury is prevented or avoided. The rodent radiation-induced renal injury model system used in Project 2 and the canine model for Gl injury (Project 1) are already well-developed; but further model development is required for large-animal renal models (Project 2), and for rodent models of Gl injury (Project 1), lung injury (Projects 3 and 4) and CNS injury (Project 5). The major pharmaceutical approaches that will be assessed are suppression of the renin-angiotensin system (Projects 1, 2, 3, 5), and suppression of acute and chronic oxidative stress (Projects 1, 2, 4, 5). The Projects will be supported by an Irradiation Core and a SOD/Catalase Mimetic Core; and the Center will also contain a Pilot Grant Program and a Teaching and Education Program).