CURRENT PREDICTIONS OF THE RISK OF RADIATION EXPOSURE INDUCED DEATH HAVE LARGE UNCERTAINTIES IN PART THIS IS BECAUSE OF POOR UNDERSTANDING OF FACTORS THAT INFLUENCE RISK IN THE LOW DOSE RANGE CORRESPONDING TO ANTICIPATED HUMAN EXPOSURE. MODELING SUGGESTS THAT THE DOSE RESPONSE MAY BE STRONGLY NONLINEAR WITH AN INCREASE IN RISK AT LOW DOSES ATTRIBUTABLE TO NON-TARGETED EFFECTS (NTES) IN CELLS NOT DIRECTLY TRAVERSED BY A RADIATION TRACK. A MODEL INCORPORATING NTES FITTED TO MOUSE HARDERIAN GLAND CARCINOGENESIS DATA PREDICTS THAT MARS MISSION CANCER RISK MAY BE TWO-FOLD GREATER THAN THAT ATTRIBUTABLE TO TARGETED EFFECTS ALONE . THESE FINDINGS HIGHLIGHT THE NEED FOR A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE HIGH RELATIVE BIOLOGICAL EFFECTIVENESS (RBE) OF GCR FOR CARCINOGENESIS INCLUDING ITS ABILITY TO ELICIT NTES. THE PRINCIPAL HYPOTHESIS FOR THIS PROPOSAL IS THAT EXPOSURE TO GCR AND PARTICULARLY ITS HIGH CHARGE AND ENERGY (HZE) PARTICLE COMPONENTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING LEADING TO DECLINE IN THE FUNCTIONAL STATUS OF THE DNA REPAIR MACHINERY AND THAT THIS IS A KEY CONTRIBUTOR TO GCR CARCINOGENESIS. PRIOR STUDIES ESTABLISH THE SCIENTIFIC PREMISE FOR THIS HYPOTHESIS AND IDENTIFY POTENTIAL UNDERLYING MECHANISMS ONE OF WHICH IS DEPLETION OF CELLULAR NAD+ POOLS AS A CONSEQUENCE OF PERSISTENT DNA DAMAGE RESULTING IN REDUCED ACTIVITY OF IMPORTANT NAD+-DEPENDENT ENZYMES. THESE INCLUDE THE DNA DAMAGE SENSING AND REPAIR FACTOR PARP1 AND PROTEIN DEACYLASES KNOWN AS SIRTUINS. EXPERIMENTS WILL INVESTIGATE THE ROLE OF THE NAD+/PARP1/SIRTUIN AXIS IN EXPERIMENTS USING BOTH HUMAN BRONCHIAL EPITHELIAL CELLS AND WILD-TYPE C57BL/6 MICE. THE WORK WILL FOCUS ON LUNG CANCER RISK AS AN ENDPOINT. SPECIFIC AIMS ARE: AIM 1. TO INVESTIGATE THE SCOPE AND MECHANISTIC BASIS FOR A GCR EXPOSURE-RELATED DECLINE IN THE FUNCTIONAL STATUS OF THE REPAIR MACHINERY USING A BRONCHIAL EPITHELIAL CELL MODEL. AIM 2.TO TEST THE HYPOTHESIS THAT GCR EXPOSURE LEADS TO A CHRONIC DNA DAMAGE RESPONSE IN MOUSE LUNG AND WHETHER THIS CAN BE ABATED WITH A DIETARY COUNTERMEASURE. WE WILL INVESTIGATE GENDER DOSE AND RADIATION QUALITY EFFECTS. AIM 3. TO DETERMINE WHETHER RADIOGENIC TUMORS DISPLAY A MUTATIONAL SIGNATURE INDICATIVE OF A DECLINE IN THE FUNCTIONAL STATUS OF THE DNA REPAIR MACHINERY AS REFLECTED IN THEIR MUTATIONAL SIGNATURE THUS ESTABLISHING A FUNCTIONAL LINK TO TUMORIGENESIS. ANTICIPATED DELIVERABLES INCLUDE RESEARCH RESULTS TO IMPROVE EVALUATION OF SEX DEPENDENCE OF RADIOGENIC LUNG CANCER; TO ALLOW FOR CALCULATION OF RBES INCLUDING MIXED FIELD RBES FOR MALES AND FEMALES PARTICULARLY AT LOW DOSES AND IN WILD TYPE BACKGROUNDS WHERE DIRECT MEASUREMENTS OF RBE FOR RADIATION-INDUCED CANCERS IS INFEASIBLE OR SUBJECT TO LARGE EXPERIMENTAL UNCERTAINTIES AND TO PERFORM AN INITIAL EVALUATION OF A POTENTIAL COUNTERMEASURE.