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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI067770-05
Application #
7676121
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (O1))
Program Officer
Ramakrishnan, Narayani
Project Start
2005-08-31
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$4,547,567
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Nielsen, Christopher E; Wang, Xihai; Robinson, Robert J et al. (2014) Carcinogenic and inflammatory effects of plutonium-nitrate retention in an exposed nuclear worker and beagle dogs. Int J Radiat Biol 90:60-70
Venkataraman, G M; Geraghty, D; Fox, J et al. (2013) Canine DLA-79 gene: an improved typing method, identification of new alleles and its role in graft rejection and graft-versus-host disease. Tissue Antigens 81:204-11
Leko, Vid; Varnum-Finney, Barbara; Li, Hongzhe et al. (2012) SIRT1 is dispensable for function of hematopoietic stem cells in adult mice. Blood 119:1856-60
Nielsen, Christopher E; Wilson, Dulaney A; Brooks, Antone L et al. (2012) Microdistribution and long-term retention of 239Pu (NO3)4 in the respiratory tracts of an acutely exposed plutonium worker and experimental beagle dogs. Cancer Res 72:5529-36
Pogosova-Agadjanyan, Era L; Fan, Wenhong; Georges, George E et al. (2011) Identification of radiation-induced expression changes in nonimmortalized human T cells. Radiat Res 175:172-84
Ivey, Richard G; Moore, Heather D; Voytovich, Uliana J et al. (2011) Blood-based detection of radiation exposure in humans based on novel phospho-Smc1 ELISA. Radiat Res 175:266-81
Mielcarek, Marco; Storb, Rainer; Georges, George E et al. (2011) Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog leukocyte antigen-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 17:214-25
Graves, Scott S; Stone, Diane M; Loretz, Carol et al. (2011) Antagonistic and agonistic anti-canine CD28 monoclonal antibodies: tools for allogeneic transplantation. Transplantation 91:833-40
Wilson, Dulaney A; Brigantic, Andrea; Morgan, William F (2011) The association of inbreeding with lung fibrosis incidence in Beagle dogs that inhaled 238PuO2 or 239PuO2. Radiat Res 176:781-6
Lee, Won Sik; Suzuki, Yasuhiro; Graves, Scott S et al. (2011) Canine bone marrow-derived mesenchymal stromal cells suppress alloreactive lymphocyte proliferation in vitro but fail to enhance engraftment in canine bone marrow transplantation. Biol Blood Marrow Transplant 17:465-75

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