FROM AN ONGOING NASA FUNDED STUDY ENTITLED PROTEOMIC SIGNATURES OF SPACE RADIATION INDUCED CARDIOVASCULAR DEGENERATION WE HAVE IDENTIFIED THAT CORNIFICATION AND KERATINIZATION PATHWAYS ARE SIGNIFICANTLY PERTURBED IN HEARTS FROM GCR IRRADIATED MICE. A FAMILY OF SMALL PROLINE RICH REPEAT PROTEINS (SPRR) ARE CENTRAL PLAYERS IN THESE PATHWAYS AND ARE ALSO ESSENTIAL PLAYERS IN REACTIVE OXYGEN SPECIES (ROS) DETOXIFICATION. THESE SPRRS ARE UPREGULATED IN VARIOUS FORMS OF TISSUE INJURY INCLUDING MYOCARDIAL INFARCTION AND BURN INJURY. AS ROS ARE CRITICAL MEDIATORS OF RADIATION INDUCED MOLECULAR AND CELLULAR INJURY WE HYPOTHESIZE THAT THE UPREGULATION OF SPRR COULD FUNCTION AS A DEFENSE MECHANISM TO MITIGATE THE DETRIMENTAL EFFECTS OF RADIATION ON THE CARDIOVASCULAR SYSTEM. TO DATE THIS CLASS OF PROTEINS HAS NOT BEEN IMPLICATED IN RADIATION INJURY. THESE PROTEINS MAY BE NOVEL CELL PROTECTIVE PROTEINS THAT MAY BE EXPLOITED AS COUNTERMEASURES FOR GCR AND OTHER TYPES OF RADIATION. USING STRATEGIES IN OUR ONGOING TRISH FUNDED GRANT ENTITLED: GENE THERAPY AS A THERAPEUTIC COUNTERMEASURE AGAINST SPACE RADIATION INDUCED CARDIOVASCULAR DEGENERATION WE WILL MOLECULARLY EXPLORE THE OVEREXPRESSION OF SEVERAL SPRR PROTEINS USING VIRAL VECTOR MEDIATED APPROACHES IN THE FOLLOWING TWO AIMS. AIM 1: DETERMINE THE EFFECTS OF ALTERED SPRR LEVELS ON CELLULAR SURVIVAL AND BIOLOGICAL FUNCTIONS IN A VARIETY OF RADIATION EXPOSURE SETTINGS. VIRAL VECTORS OVER-EXPRESSING OR DOWN-REGULATING SPRRS WILL BE DEVELOPED AND UTILIZED IN A VARIETY OF CELL MODELS TO ASSESS THE IMPACT OF INDIVIDUAL MODULATION ON A VARIETY OF BIOLOGICAL OUTCOMES POST-RADIATION TREATMENT. THIS AIM WILL TEST OUR HYPOTHESIS THAT MODULATION SUCH AS OVER-EXPRESSION OF ANY OF THESE PROTEINS WILL PROVIDE RESISTANCE TO RADIATION EXPOSURE AND WILL PROVIDE A QUICK MEANS OF DOWN-SELECTION OF THE TARGETS. RADIATION EXPOSURE EXPERIMENTS WILL OCCUR AT THE INSTITUTION. AIM 2: DETERMINE THE EFFECTS OF MODULATION OF SPRR LEVELS ON ANIMAL SURVIVAL OR PHYSIOLOGY FOLLOWING EXPOSURE TO GCR AT BNL. USING VIRAL VECTORS BASED ON THE SPRR PROTEINS DOWN-SELECTED IN AIM 1 THE INSTITUTION WILL TEST THE HYPOTHESIS THAT CHOSEN VIRAL VECTORS WHEN ADMINISTERED SYSTEMICALLY OR TO TARGETED ORGANS SUCH AS THE HEART OR BRAIN WILL CONFER OVERALL OR ORGAN SPECIFIC RESILIENCE TO RADIATION EXPOSURE.