UNC-CH SUBCONTRACT Abstract This application focuses on a central goal of the RFA for Centers for Medical Countermeasures Against Radiation to “further develop existing as well as novel therapies to minimize tissue damage, hasten tissue recovery, restore normal physiological function, and improve survival.” Multi-organ radiation-induced injury is a major threat during targeted terror attack, and adaptive and innate immunity are increasingly found to play a key role in this process. Innate immune receptors collectively referred to as Pathogen Recognition Receptors (PRR) have undergone an explosive discovery phase. Prominent PRR families include the membrane bound Toll-like receptors (TLR) which interact with extracellular ligands. These have been extensively studied in infection and inflammatory diseases, and their impact on radiation-induced damage has emerged in the last few years. Post-exposure, radiation not only causes acute injury but also delayed injury such as fibrosis and defective cellular and immune development. We and others have explored the roles of TLRs in radiation and unexpectedly found that certain TLRs and their ligands are protective of radiation-induced damage involving both the hematopoietic system as well as the gastrointestinal tissues. In addition to TLR ligands, we have also isolated beneficial microbiota and metabolites from animals that survived lethal radiation, and propose to explore if these microbes and their metabolites can mitigate radiation damage. This proposal will focus on the use and mechanism of TLR ligands, commensal microbes and their metabolites as radiation mitigators that can reduce radiation induced damage.