LONG-TERM EXPOSURE TO THE WEIGHTLESS ENVIRONMENT CAUSES ASTRONAUTS TO BECOME SICK AND DEVELOP ISSUES LIKE CONSTIPATION SKIN RASHES AND INCREASED LIKELIHOOD OF DEVELOPING A COLD. THIS MICROGRAVITY ENVIRONMENT ALSO INDUCES A REDISTRIBUTION OF BODILY FLUIDS TOWARDS THE HEAD. THIS FLUID REDISTRIBUTION CAUSES THEIR HEART AND CIRCULATORY SYSTEM (I.E. THE ARTERIES VEINS AND LYMPHATIC VESSELS THAT TRANSPORT BLOOD AND LYMPH THROUGHOUT THE BODY) TO WORK DIFFERENTLY. NO ONE HAS EXPLORED WHETHER THE INCREASED LIKELIHOOD OF ASTRONAUTS DEVELOPING COLDS/BEING SICK IS LINKED TO CHANGES IN HOW THE CARDIOVASCULAR SYSTEM FUNCTIONS IN SPACEFLIGHT. THIS IS A CONCERN AS HOW THE IMMUNE SYSTEM (WHICH IS RESPONSIBLE FOR MAKING SURE YOUR BODY STAYS HEALTHY) FUNCTIONS IS LINKED TO HOW WELL COMPONENTS OF THE IMMUNE SYSTEM CAN TRAVEL THROUGHOUT THE BODY THROUGH THE CIRCULATION. THEREFORE OUR GENERAL HYPOTHESIS IS THAT AN INABILITY FOR COMPONENTS OF THE IMMUNE SYSTEM TO CIRCULATE NORMALLY CAUSES THE INCREASED LIKELIHOOD OF ASTRONAUTS BECOMING SICK AS WELL AS ALSO PLAYING A ROLE WITH HOW THE CIRCULATORY SYSTEM ADAPTS TO A WEIGHTLESS ENVIRONMENT DUE TO THE CONSEQUENCES OF IMPAIRED IMMUNITY. WE WILL TEST THIS HYPOTHESIS IN THE GOLD-STANDARD RODENT MODEL FOR SIMULATING MICROGRAVITY EFFECTS ON EARTH THE HINDLIMB-UNLOADING (HU) MODEL. USING HU WE WILL TEST LONG-TERM SIMULATED MICROGRAVITY EFFECTS ON THE DIGESTIVE AND HINDLIMB SYSTEMS OF THE RODENTS FOR THEIR CHANGES IN IMMUNE FACTORS AND CIRCULATORY SYSTEM RESPONSES. THIS WILL BE DONE UTILIZING TECHNIQUES THAT CAN MEASURE A BROADSPECTRUM OF IMMUNE FACTORS IN THE TISSUES FROM THE DIGESTIVE SYSTEM AND HINDLIMB TO IDENTIFY THE MOST RELEVANT TARGET(S) THAT COULD INFLUENCE ALTERED IMMUNE RESPONSE AND CHANGES IN CIRCULATORY FUNCTION. FURTHERMORE WE WILL TEST THE FUNCTION OF THE ARTERIES VEINS AND LYMPHATICS IN THE DIGESTIVE AND HINDLIMB SYSTEMS TO COMPARE RESPONSES BETWEEN THE TWO ORGAN BEDS IN RESPONSE TO LONG-TERM SIMULATED MICROGRAVITY. FINALLY WE HAVE DISCOVERED A NOVEL THERAPEUTIC ANTI-INFLAMMATORY AGENT IRISIN THAT WE HAVE SHOWN IN OTHER RODENT MODELS OF IMPAIRED IMMUNITY TO RESOLVE AND BENEFICIALLY IMPROVE OUTCOMES OF DIGESTIVE AND HINDLIMB STRUCTURE FUNCTION AND IMMUNE STATE. WE WILL USE IRISIN AS A COUNTERMEASURE IN OUR SIMULATED MICROGRAVITY STUDIES TO TREAT THE PREDICTED IMMUNE-DRIVEN CIRCULATORY CHANGES IN THE DIGESTIVE AND HINDLIMB SYSTEMS FOR OUR LONG-TERM GOAL OF A TREATMENT THAT CAN HOLISTICALLY TREAT ASTRONAUTS AND DISEASE CONDITIONS ON EARTH. THESE STUDIES INVESTIGATE NOVEL AND UNEXPLORED MECHANISMS BIOLOGICAL RESPONSES AND TREATMENTS IN RELATION TO NASA SPACE BIOLOGY'S GOALS TO UNDERSTAND THE BASIC MECHANISMS THAT ANIMALS USE TO ADAPT/ACCLIMATE TO SPACEFLIGHT AND TO CONTRIBUTE BASIC KNOWLEDGE OF BIOLOGICAL ADAPTATION/ACCLIMATION TO SPACEFLIGHT THAT MAY ACCELERATE SOLUTIONS TO BIOMEDICAL PROBLEMS AFFECTING HUMAN SPACE EXPLORATION AS WELL AS HUMAN HEALTH ON EARTH. WE WILL DISCOVER NEW KNOWLEDGE ADDRESSING TOPICS OF INTEREST INCLUDING IMMUNOLOGY MUSCULOSKELETAL CHANGES DIGESTIVE SYSTEM CHANGES VASCULAR AND LYMPHATIC DRAINAGE AND ADAPTATION OF LIFE TO SPACE. INDEED THROUGH SUPPORT OF THESE RESEARCH AIMS WE WILL DISCOVER NEW KNOWLEDGE AND THERAPIES FOR THE BENEFIT OF HUMAN SPACE EXPLORATION AND BIOMEDICAL PROBLEMS ON EARTH.