UNC-CH SUBCONTRACT Abstract This application focuses on a central goal of the RFA for Centers for Medical Countermeasures Against Radiation to ?further develop existing as well as novel therapies to minimize tissue damage, hasten tissue recovery, restore normal physiological function, and improve survival.? Multi-organ radiation-induced injury is a major threat during targeted terror attack, and adaptive and innate immunity are increasingly found to play a key role in this process. Innate immune receptors collectively referred to as Pathogen Recognition Receptors (PRR) have undergone an explosive discovery phase. Prominent PRR families include the membrane bound Toll-like receptors (TLR) which interact with extracellular ligands. These have been extensively studied in infection and inflammatory diseases, and their impact on radiation-induced damage has emerged in the last few years. Post-exposure, radiation not only causes acute injury but also delayed injury such as fibrosis and defective cellular and immune development. We and others have explored the roles of TLRs in radiation and unexpectedly found that certain TLRs and their ligands are protective of radiation-induced damage involving both the hematopoietic system as well as the gastrointestinal tissues. In addition to TLR ligands, we have also isolated beneficial microbiota and metabolites from animals that survived lethal radiation, and propose to explore if these microbes and their metabolites can mitigate radiation damage. This proposal will focus on the use and mechanism of TLR ligands, commensal microbes and their metabolites as radiation mitigators that can reduce radiation induced damage.
UNC-CH SUBCONTRACT Narrative This application focuses on a central goal of the RFA for Centers for Medical Countermeasures Against Radiation by developing an existing, experimental radio-mitigator and by discovering new therapies to minimize radiation induced damage and to enhance survival.
|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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