Project Abstract Currently, there is a need for drugs that mitigate acute radiation induced gastrointestinal syndrome (RIGS). Risk of large populations encountering radiation exposure is real and growing due to the proliferation of rogue nonstate actors, political instability resulting in potential access of nuclear weapons by terrorist, and by natural disaster as evidenced by the release of radioactive material from the Fukushima nuclear power plant in early 2011. Currently, Neupogen®, Nulasta® (filgrastim) and Leukine™ (sargramostim) are the only FDA approved agents available and only for the management of Hematopoietic Acute Radiation Syndrome. Due to radio- sensitivity of intestinal epithelium, RIGS is the major cause of death from acute radiation syndrome at high radiation doses and no drugs are approved at this time. The current options for mitigating tissue damage and mortality of a large population after exposure to radiation are currently an un met need with approved drugs unable to fill the gap. Moreover, high radio-sensitivity of intestinal epithelium increases susceptibility to radiation induced gastrointestinal syndrome ( RIGS) and induces mortality rapidly within 3-10 days post radiation, leaving very limited time for therapeutic intervention. We have demonstrated that treatment with BCN057 at 24hrs post radiation exposure can mitigate RIGS by accelerating intestinal epithelial repair with the activation of Wnt-β catenin signaling and improves survival following lethal dose of irradiation. Intestinal epithelial repair process is dependent on induction of proliferation of residual intestinal stem cells. we hypothesized that BCN057 will have a general applicability to mitigate RIGS when delivered hours after radiation exposure. In this proposal we will characterize the most effective dose and schedule for administration of BCN057 to mitigate RIGS in mice. This will include Identifying the optimal dose and schedule of BCN057 when given at 24 hr post exposure to mitigate RIGS in adult mice; Identify the time to dosing beyond 24 hr at which BCN057 can still improve survival; Define the radiation dose modifying factor for BCN057 treatment and verify biological variability in radiosensitive and gender context. For Specific Aim 1 we will characterize dose proportionality, dose regimen and dose response of BCN057 for mitigation of Radiation Induced Gastro Intestinal Syndrome by the FDA animal rule. In Specific Aim2, we will assess time to dosing at 48 and 72 hours, age differences using young and old mice, genetic radio sensitive and resistance, a phenomenon highly exhibited in adult humans using (Balc and C57). Together these studies will demonstrate the utility of BCN057 as a mitigator of RIGS as well as model response behavior to advance its use for countermeasures and clinical use.