PROJECT SUMMARY: Ionizing radiation causes double strand breaks and damages the protein-based mechanisms responsible for their repair. This makes mitotic cells in the bone marrow, gut and reproductive organs highly susceptible to ionizing radiation damage. In addition, as humans age, we become more susceptible to the effects of radiation likely due to inherent accumulated cellular damage we accrue over time. There are very few pharmaceutical countermeasures approved for mitigation of acute radiation damage, and none are effective for prophylactic intervention. Given the use of nuclear power plants, the proliferation of nuclear arms and increased global interest in space flight with its concomitant cosmic ray exposure, there is a pressing need to identify medicinal sources of radioprophylactics. Fungi are sources of diverse and powerful pharmaceuticals, and many strains of fungi are remarkably radioresistant. Various fungi have been found growing in the heavily irradiated environments of the Chernobyl Nuclear Power Plant and the International Space Station. To meet the growing need for radioprophylactics, we seek to determine the radioprotective efficacy of dietary administration of highly radiation-resistant non- pathogenic fungi. Drosophila are natural fungivores. In addition, Drosophila are an excellent model system in which to study the damaging effect of radiation exposure on various organ systems since they share many similarities with vertebrates yet are easily manipulated with sophisticated genetics and cell biology. We hypothesize that consumption of these fungal strains will increase resistance to acute radiation damage through known and unidentified factors. To do this, we will feed three Drosophila genotypes a panel of highly radioresistant fungi. In addition to wild type flies, we will also test whether radioresistant fungi confer radiation resistance to two mutant Drosophila strains that accumulate oxidative damage. To test our hypothesis, we propose a single Aim. We will exposure the flies to gamma irradiation and test if the selected dietary fungi confer radioprotection to lifespan, the gastrointestinal tract, the ovary, and various biomolecules. We expect to find a radioprotective effect of dietary radioresistant fungi at one or several levels of our studies from organismal to molecular. Knowledge gained from this research will open the opportunity to screen hundreds of fungi using a relatively simple method. Once protective fungal strains are identified, future studies can test their effectiveness in vertebrates, as well as identify the molecules responsible.