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.
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