The toxicity of ionizing radiation (IR) in diverse cell-types is associated with a high susceptibility of the proteome to oxidative modification. Proteome protection as a tactic for IR survival was recently applied to mice using a synthetic Mn-peptide antioxidant complex (MDP) that specifically prevents protein oxidation and preserves the activity of irradiated enzymes, including those for cellular DNA repair. MDP, adapted from the radioresistant bacterium Deinococcus radiodurans , is nontoxic and protects mice from acute radiation syndromes (ARS). When administered pre- and post-irradiation, all the mice treated with MDP survived 9.5 Gy (LD70/30). MDP diminished ARS and increased serum levels of IL-3, G-CSF and GM-CSF. The radioprotective efficacy of MDP administered to mice post-irradiation, however, remains untested. Note, there is good reason to think that post-exposure treatment alone with MDP will be radioprotective: MDP protects human Jurkat T-cells exposed to 100 Gy when administered 4 hours post-irradiation. We propose to determine whether MDP could serve as an IR countermeasure when administered starting 24, 48, or 72 hours after exposure to x-ray irradiation. The MDP complex will be tested in a standard mouse model for total body irradiation induced ARS (controlled for age and diet), focusing on tissue- and immunological-functions among the survivors.
Public Health Relevance Statement: Potential radiological exposure from terrorist acts, nuclear warheads, and power plant accidents have been a continual source of concern to scientists, politicians, and the general populace. No drugs have been approved that mitigate lethal exposures and lead to survival. We propose to assess a manganese-decapeptide-phosphate (MDP) complex that protects all proteins from ionizing radiation damage under aqueous conditions. The MDP complex has been shown to protect surface proteins of bacteria and viruses in vaccine discovery studies and preliminary results demonstrate its protective efficacy when administered to mice prior to exposure. We propose to determine whether or not MDP can protect mice from lethal irradiation when administered starting 1, 2 or 3 days following irradiation. Further, we propose to examine the protective efficacy of MDP on organ tissues and the immune system. Successful conclusion of this SBIR Phase I project will lead to continued develop through a potential Phase II and then IND-enabling studies.
Project Terms: Accidents; Age; Animal Model; Animals; Antioxidants; aqueous; Bacteria; bacterial resistance; Biomimetics; cell type; Cells; cellular targeting; commercialization; Complex; Cooperative Research and Development Agreement; CSF3 gene; Deinococcus; Deinococcus radiodurans; Desiccation; design; Diet; DNA Damage; DNA Repair; Dose; Enzymes; Event; Exposure to; Female; Free Radicals; Gamma Rays; Genome; Granulocyte-Macrophage Colony-Stimulating Factor; Hematology; Histopathology; Hour; Human; immune function; Immune system; Immunize; Immunocompetence; improved; In Vitro; inorganic phosphate; Interleukin-3; Ionizing radiation; irradiation; Lead; Mammalian Cell; Manganese; manganese chloride; Medical; Membrane Proteins; Modeling; Modification; mouse model; Mus; Names; neutralizing antibody; Nuclear; Oral; Organ; Orthophosphate; Outcome Measure; oxidation; Peptides; Pharmaceutical Preparations; Phase; phase 1 study; Phosphate Buffer; Poliomyelitis; Poliovirus Vaccines; Potassium Phosphate; Power Plants; Predisposition; prevent; primary outcome; Process; protective efficacy; Proteins; Proteome; Radiation exposure; Radiation induced damage; Radiation Toxicity; Radiology Specialty; Radioprotection; radioresistant; Reactive Oxygen Species; Recovery; Reporting; Research; Resistance; Roentgen Rays; Scientist; secondary outcome; Serum; Services; sex; Small Business Innovation Research Grant; small molecule; Source; Superoxide Dismutase; Survivors; T-Lymphocyte; Testing; Tissues; Toxic effect; Treatment Efficacy; Ultraviolet C Radiation; Universities; vaccine discovery; Virus; Weight Gain; Whole-Body Irradiation
