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.
|Mont, Stacey; Davies, Sean S; Roberts Second, L Jackson et al. (2016) Accumulation of isolevuglandin-modified protein in normal and fibrotic lung. Sci Rep 6:24919|
|Hanbury, David B; Peiffer, Ann M; Dugan, Greg et al. (2016) Long-Term Cognitive Functioning in Single-Dose Total-Body Gamma-Irradiated Rhesus Monkeys ( Macaca mulatta ). Radiat Res 186:447-454|
|Koechlein, Claire S; Harris, Jeffrey R; Lee, Timothy K et al. (2016) High-resolution imaging and computational analysis of haematopoietic cell dynamics in vivo. Nat Commun 7:12169|
|DeBo, Ryne J; Lees, Cynthia J; Dugan, Greg O et al. (2016) Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques. Radiat Res 186:55-64|
|Batinic-Haberle, Ines; Tovmasyan, Artak; Spasojevic, Ivan (2015) An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins--From superoxide dismutation to H2O2-driven pathways. Redox Biol 5:43-65|
|Gomez, John C; Yamada, Mitsuhiro; Martin, Jessica R et al. (2015) Mechanisms of interferon-Î³ production by neutrophils and its function during Streptococcus pneumoniae pneumonia. Am J Respir Cell Mol Biol 52:349-64|
|Hanbury, David B; Robbins, Mike E; Bourland, J Daniel et al. (2015) Pathology of fractionated whole-brain irradiation in rhesus monkeys ( Macaca mulatta ). Radiat Res 183:367-74|
|Krauss, Jennifer L; Zeng, Rong; Hickman-Brecks, Cynthia L et al. (2015) NLRP12 provides a critical checkpoint for osteoclast differentiation. Proc Natl Acad Sci U S A 112:10455-60|
|Johnson, Jason N; Hornik, Christoph P; Li, Jennifer S et al. (2015) Response to letters regarding article, "Cumulative radiation exposure and cancer risk estimation in children with heart disease". Circulation 131:e419-20|
|Cheong, Woo-Chang; Kang, Hye-Ri; Yoon, Hyunyee et al. (2015) Influenza A Virus NS1 Protein Inhibits the NLRP3 Inflammasome. PLoS One 10:e0126456|
Showing the most recent 10 out of 178 publications