The hematopoietic and immune systems are highly sensitive to the adverse effects of ionizing radiation. After relatively low level exposures (< 100 cGy total body), chromosomal aberrations in lymphocytes can be measured as well as decline in the white blood cell and platelet count. At levels of 200-400 cGy, marked leukopenia, lymphopenia, anemia, and thrombocytopenia can occur and 50% of those exposed to 400 cGy will die absent proper medical intervention. At higher levels of exposure (>400 - 1000 cGy), gastrointestinal and other organ toxicities can be seen, but the greatest risk to such patients is persistent failure of the hematopoietic and immune systems, resulting in life threatening complications (infections, bleeding). Unfortunately, specific therapies directed at accelerating the repair and recovery of the hematopoietic and immune systems following radiation injury have been few. In this project, we aim to characterize the capacity for human growth hormone (HGH), a recombinant product already in human use, to ameliorate the hematopoietic toxicities and immune failure that occur following radiation injury. HGH has postulated roles in stimulating thymopoiesis, lymphocyte recovery, erythropoiesis and granulopoiesis. However, its activity toward promoting the rapid recovery of the immunohematopoietic system after radiation exposure has not been demonstrated. In this project we will a) examine and characterize the activity of HGH to accelerate hematopoietic recovery in animals recently exposed to several levels of radiation and will determine whether HGH exerts its effect via hematopoeitic stem cell self-renewal or progenitor cell activation, b) characterize the activity of HGH toward recovering T and B cell function and thymopoiesis following radiation injury, and c) test these hypotheses in a large animal cynomolgus monkey model of radiation injury. Our overriding goal will be the demonstration of the unique radiotherapeutic capacity of HGH, a recombinant product ideally suited for addition to the National Stockpile of radiation countermeasures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI067798-02
Application #
7310443
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$281,565
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Cline, John Mark; Dugan, Greg; Bourland, John Daniel et al. (2018) Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation. Antioxidants (Basel) 7:
Farris, Michael; McTyre, Emory R; Okoukoni, Catherine et al. (2018) Cortical Thinning and Structural Bone Changes in Non-Human Primates after Single-Fraction Whole-Chest Irradiation. Radiat Res 190:63-71
Naqvi, Ibtehaj; Gunaratne, Ruwan; McDade, Jessica E et al. (2018) Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis. Mol Ther 26:1020-1031
Ghandhi, Shanaz A; Turner, Helen C; Shuryak, Igor et al. (2018) Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells. PLoS One 13:e0191402
Castle, Katherine D; Daniel, Andrea R; Moding, Everett J et al. (2018) Mice Lacking RIP3 Kinase are not Protected from Acute Radiation Syndrome. Radiat Res 189:627-633
Fanning, K M; Pfisterer, B; Davis, A T et al. (2017) Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling. Am J Physiol Regul Integr Comp Physiol 313:R290-R297
Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626
Kurkjian, Cathryn J; Guo, Hao; Montgomery, Nathan D et al. (2017) The Toll-Like Receptor 2/6 Agonist, FSL-1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome. Sci Rep 7:17355
Racioppi, Luigi; Lento, William; Huang, Wei et al. (2017) Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis 8:e3076
Himburg, Heather A; Doan, Phuong L; Quarmyne, Mamle et al. (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91-99

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