THE GOALS OF THIS RESEARCH PROPOSAL ALIGN WITH NASA S EMPHASIS ON ANIMAL BIOLOGY (VERTEBRATES) IN SUPPORT OF HUMAN SPACE EXPLORATION AND THE CELL AND MOLECULAR BIOLOGY GUIDING QUESTIONS 1 5 AND 8 (TO DEFINE THE UNDERLYING MECHANISMS OF THE CELLS THAT ARE INFLUENCED BY GRAVITATIONAL CHANGES CAUSING TISSUE/ORGAN DYSFUNCTION AND AFFECT STEM CELL FUNCTION RESPECTIVELY) AS DESCRIBED AT THE SPACE BIOLOGY SCIENCE PLAN 2016-2025. THIS WORK IS HIGHLY RELEVANT TO THE CARE OF ASTRONAUTS SINCE WE ANTICIPATE THAT OUR RESULTS WILL HELP UNDERSTAND THE IMPORTANCE OF TELOMERE LENGTH ALTERATIONS IN STEM CELLS DURING SKELETAL MUSCLE ATROPHY THAT HAVE NOT BEEN STUDIED BEFORE. OUR STUDY WILL BENEFIT NASA AND ASTRONAUTS HEALTH BY 1) EVALUATING THE COMBINED EFFECT OF WEIGHTLESSNESS AND RADIATION EXPOSURE ON TELOMERE LENGTH IN MUSCLE ATROPHY AND 2) ASSESSING THE MOLECULAR PATHWAYS AFFECTED DURING THIS PROCESS. OVERALL BY COMBINING UNIQUE MOLECULAR AND CELLULAR BIOLOGY APPROACHES AS WELL AS GENETICALLY ENGINEERED MICE THAT OUR LAB HAS DEVELOPED WE WILL DETERMINE THE MOLECULAR MECHANISMS OF TELOMERE DEFECTS IN MUSCS OF ATROPHIED MUSCLES THAT CAN TRANSLATE INTO BENEFITS FOR NASA EXPLORATION MISSION. THE REGULATORY MECHANISMS THAT WE WILL EXPLORE IN THIS PROPOSAL USING PROVEN ANALOGS SUCH AS MOUSE HIND LIMB UNLOADING THAT INDUCE BIOLOGICAL EFFECTS SIMILAR TO SPACEFLIGHT WILL BE FUNDAMENTAL FOR FUTURE STUDIES TO INVESTIGATE MUSCLE SPECIFIC TELOMERE LENGTH CHANGES IN TRANSITIONS FROM ONE GRAVITY TO ANOTHER. ADDITIONALLY SUCCESS IN OUR EXPERIMENTS WILL INFORM SIMILAR MECHANISMS IN MUSCULOSKELETAL APPLICATIONS WITH STEM CELL DYSFUNCTION SUCH AS MUSCLE INJURIES AFTER REPEATED EXERCISES PROVIDING BENEFITS TO THE HEALTH AND WELL BEING TO BOTH ASTRONAUTS IN SPACE AND THOSE ON EARTH.