SPACEFLIGHT BY IMPAIRING THE DIFFERENTIATION PROGRAM OF STEM CEUS RESIDING WITHIN BONE MARROW RESULTS IN BONE LOSS INCREASED BONE MARROW ADIPOSITY ANEMIA AND IMPAIRED IMMUNE FUNCTION. BECAUSE THESE DISTURBANCES MAY POTENTIALLY COMPROMISE THE SUCCESS OF LONG-DURATION FLIGHTS THERE EXISTS AN URGENT NEED TO IDENTIFY THE UNDERLYING MECHANISMS AND IMPLEMENT EFFECTIVE COUNTERMEASURES. WE PROPOSE TO TEST THE NOVEL HYPOTHESIS THAT NEGATIVE ENERGY BALANCE DURING SPACEFLIGHT RESULTS IN 1) BONE MARROW DYSFUNCTION ANDINCREASED MARROW ADIPOSITY AND 2) ALTERED SIGNALING BY PERIPHERAL ADIPOKINES (CYTOKINES PRODUCED BY ADIPOCYTES) ALL OF WHICH IN TURN CONTRIBUTE TO NEGATIVE BONE TURNOVER BALANCE AND BONE LOSS. THE PROPOSED RESEARCH WILL FOCUS ON THE PRECISE ROLE OF ADIPOSE TISSUE AND THE IMPORTANT ADIPOKINE LEPTIN IN MEDIATING THE DETRIMENTAL EFFECTS OF SIMULATED SPACEFLIGHT (HINDLIMB UNLOADING) ON BONE MARROW CELLS IN MICE BY ACCOMPLISHING THE FOLLOWING 2 SPECIFIC AIMS: SPECIFIC AIM 1 WILL TEST THE HYPOTHESIS THAT INCREASED BONE MARROW ADIPOSITY PLAYS A CAUSAL ROLE IN MEDIATING SIMULATED SPACEFLIGHT-INDUCED CHANGES IN BONE METABOLISM. THIS WILL BE ACCOMPLISHED BY COMPARINGTHE SKELETAL RESPONSE TO HINDLIMB UNLOADING OF WILD TYPE (WT) MICE WITH MICE INCAPABLE OF GENERATING BONE MARROW ADIPOCYTES (KIT-RECEPTOR-DEFICIENT KITW7W-V MICE). SPECIFIC AIM 2 V/ILL TEST THE HYPOTHESIS THAT THE ADIPOTDNE LEPTIN BY TARGETING THE DIFFERENTIATION OF BONE MARROW STEM CELLS PLAYS A KEY ROLE IN MEDIATING ENERGY SENSITIVE CHANGES IN BONE METABOLISM DURING SIMULATED SPACEFIIGHT. THIS WILL BE ACCOMPLISHED BY EXAMINING WHETHER TRANSPLANTATION OF MESENCHYMAL OR HEMATOPOIETIC STEM CELLS FROM LEPTINRECEPTOR-DEFICIENT DB/DB MICE INTO WT MICE ALTERS BONE LOSS DURING SIMULATED SPACEFIIGHT. COMPLETION OF THE PROPOSED PROJECT IS EXPECTED TO INCREASE OUR UNDERSTANDING OF THE ROLE OF ENERGY METABOLISM IN MEDIATING BONE LOSS DURING SIMULATED SPACEFLIGHT AND SUGGEST SPECIFIC NON-PHARMACOLOGICAL AND PHARMACOLOGICAL INTERVENTIONS TO MITIGATE THE DETRIMENTAL EFFECTS OF SPACEFLIGHT ON BONEMARROW.