Ionizing irradiation-induced cutaneous injury is a major component of fission bomb/dirty bomb dispersal of beta and gamma irradiation emitting isotopes. Radiological dispersion device (RDD) "dirty bomb" events are associated with both thermal burn and radiation burn of victims in the blast area. In particular, beta-a particle radiation from isotopic fallout irradiation produces significant cutaneous injury. Common measures currently utilized to treat ionizing irradiation/thermal burns focus on available topical agents and strategies based primarily on experience with thermal burn injury. Development of new topically administered agents to prevent or mitigate ionizing irradiation- induced skin damage is desperately needed, particularly because of the concern for fallout irradiation to populations distant from the area associated with thermal burns. We have demonstrated that mitochondrial targeting of hemigramacidin-linked nitroxides, and other small molecule agents that stabilize mitochondrial membranes and cardiolipin/cytochrome C interaction, can ameliorate ionizing irradiation-induced damage in the organ specific, total body irradiation C57BL/6J mouse model. Through this project, we will develop and characterize the capacity of topically applied small molecule mitochondrial targeted antioxidants to prevent or mitigate radiation induced damage in skin. To accomplish this we have assembled a multidisciplinary team of investigators with well established expertise in radiation biology, chemistry, pharmacology, and skin biology. We will utilize the unique synergies that the combined experience and skills of this investigative team affords to develop mitochondrial targeted small molecule radioprotectants/mitigators, and topical formulations designed to deliver therapeutic levels of these drugs into the skin. We will evaluate delivery and the functional effectiveness of these compounds in preventing and/or mitigating radiation induced skin damage in murine models. Importantly, in pre-clinical translational studies we will use our novel living human skin explant system to evaluate drug delivery and the functional effectiveness of these compounds in preventing or mitigating radiation induced skin damage in living human skin. These in vitro living human skin studies are designed as a direct prelude to in vivo clinical testing and eventual clinical application of these novel strategies to prevent or mitigate radiation induced skin damage.