OUR OVERALL OBJECTIVE IS TO DETERMINE THE SHORT- AND LONG-TERM RISKS OF RADIATION FROM THE SPACE ENVIRONMENT ON COGNITION MOTOR ABILITIES FATIGUE RESISTANCE ANXIETY AND CHANGES IN THE BRAIN AND CARDIOVASCULAR SYSTEM. OVER THE PAST 3 YEARS WE HAVE DETERMINED THAT LOW-DOSE 56FE (IRON) RADIATION HAS LONG-TERM SEX-SPECIFIC CONSEQUENCES ON COGNITION LOCOMOTION NEUROINFLAMMATION AND ALZHEIMERS DISEASE (AD) PATHOGENESIS WITH MALES BEING MORE VULNERABLE THAN FEMALES. ANALYSIS OF PROTON-IRRADIATED MICE IS UNDERWAY. OVER THE PAST YEAR WE HAVE DEVELOPED A COLLABORATION WITH DR. DORIS TAYLOR (TEXAS HEART INSTITUTE) CO-I ON THIS PROPOSAL BY SHARING THE HEART ONE KIDNEY AND BONE MARROW FROM EACH OF THE MICE IRRADIATED IN THREE OF OUR STUDIES. OVER THE NEXT 4 YEARS WE WILL EXTEND OUR RESEARCH BY COMPARING OUR EXISTING DATA FROM OUR CURRENT STUDIES ON THE LATE CENTRAL NERVOUS SYSTEM (CNS) AND CARDIOVASCULAR (CV) EFFECTS OF A SINGLE DOSE OF IRON RADIATION OR A SINGLE DOSE OF PROTONS WITH A SINGLE DOSE OF OXYGEN-16 OR MIXED BEAM GCR (PROTONS OXYGEN-16 AND IRON) IN MALE AND FEMALE AD-LIKE TRANSGENIC AND WILDTYPE MICE AND GAMMA IRRADIATED WILDTYPE MICE (AIM 1). IN ADDITION WE WILL EXAMINE THE SEX- AND APO E-SPECIFIC LATE CNS AND CV DOSE-SPECIFIC EFFECTS OF IRON RADIATION IN THE SAME AD-LIKE MOUSE MODEL MODIFIED BY TARGETED REPLACEMENT OF MURINE APO E WITH HUMAN APO E3 OR E4 TO DETERMINE IF HUMAN APOE4 A STRONG RISK FACTOR FOR AD AND CV DISEASE EXACERBATES THE EFFECTS OF RADIATION (AIM 2). THIS WORK WILL BE CONDUCTED IN COLLABORATION WITH INVESTIGATORS AT WASH U DUKE U AND NYU. WE WILL PERFORM LONGITUDINAL MAGNETIC RESONANCE IMAGING (MRI) ON THE BRAIN AND HEART IN A SUBSET OF MICE IN AIMS 1 AND 2 TO DETERMINE RADIATION-INDUCED CHANGES WITHIN INDIVIDUAL ANIMALS. IN ADDITION MICE WILL UNDERGO EXTENSIVE BEHAVIORAL TESTING AS WELL AS PATHOLOGICAL AND BIOCHEMICAL ANALYSIS OF BRAIN AND HEART. LASTLY WE WILL CONDUCT A STUDY TO TEST 2 NOVEL HUMAN 3D NEURAL ORGANOID MODELS OF ALZHEIMERS DISEASE DEVELOPED BY OUR COLLABORATORS AT MGH AND MIT (AIM 3) FOR ACUTE AND LATE CNS EFFECTS OF SPACE RADIATION ON NEURONAL HEALTH AMYLOID PLAQUES TAU PATHOLOGY AND EPIGENETICS AND TO INVESTIGATE THE POTENTIAL OF THESE MODELS FOR SCREENING MITIGATING TREATMENTS IN THE FUTURE. IN COLLABORATION WITH DR. TAYLOR WE WILL ALSO IRRADIATE UNDIFFERENTIATED INDUCED PLURIPOTENT STEM CELLS (IPSCS) FROM HUMAN MALES AND FEMALES TO DETERMINE WHETHER HIGHLY CHARGED HIGH ENERGY (HZE) PARTICLE IRRADIATION ALTERS THEIR ABILITY TO DIFFERENTIATE INTO CARDIOMYOCYTES MORPHOLOGY AND/OR MATURATION. IN SUMMARY WE PROPOSE TO TAKE OUR CURRENT STUDIES TO THE NEXT LOGICAL STEP IN AN EFFORT TO BETTER UNDERSTAND THE POTENTIAL RISKS OF GALACTIC COSMIC RADIATION (GCR) TO THE BRAIN AND CARDIOVASCULAR SYSTEM IN ORDER TO PREPARE ASTRONAUTS FOR LONG-TERM DEEP SPACE MISSION INCLUDING MISSIONS TO MARS.