The goal of this project is to finalize the development of an effective, practical, and widely available medical countermeasure to mitigate and/or treat radiation-induced lung injury using a metalloporphyrin antioxidant compound, MnTnHex-2-PyP5+ developed during the last funding period. The rationale for metalloporphyrin mimetics as medical countermeasures arises from well-characterized pathophysiological pathways, which rely on redox signaling, that underiy the development of radiation-induced lung injury. In the previous funding period the ability of MnTnHex-2-PyP5+ to effectively mitigate radiation-induced lung injury was demonstrated in both rodent and in non-human primate models when given at relatively low doses (0.05 mg/kg). Based on these studies, we now propose in collaboration with the Primate Core, to perform dose escalation studies to determine the optimum subcutaneous dose of MnTnHex-2-PyP5+ to improve lung function and survival after whole thorax irradiation in a NHP model (Specific Aim 1). At the same time we recognize the need for improved delivery techniques. Therefore, Specific Aim 2 is focused on development of an oral formulation of MnTnHex-2-PyP5+ which will be first tested in our rodent model (optimum dose, duration, and window of opportunity for treatment initiation) prior to efficacy studies in our NHP model, which will occur in the last year of the new funding period. Lastly, parallel studies will be conducted to determine the mechanism of action of MnTnHex-2-PyP5+ . If successful, this project will provide a safe and effective deliverable that can be stockpiled and made widely available for use in mass casualty settings after an accidental or deliberate radiation emergency.
The most important components of acute radiation sickness are the hematopoietic and gastrointestinal syndromes. However, experience suggests one of the primary concerns associated with the exposure to upper half body or total body irradiation is an acute but delayed onset of radiation pneumonitis with an incidence that rises very steeply at relatively low radiation doses. Therefore, the goal of this project is to develop a safe and effective medical countermeasure against radiation-induced lung injury.
|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|
|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|
|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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