APPROXIMATELY 8% OF THE HUMAN GENOME IS COMPOSED OF ENDOGENOUS RETROVIRUS (ERVS). THESE GENETIC ELEMENTS HAVE HELPED SHAPE HUMANS AS THEY EXIST TODAY. ERVS ARE NORMALLY MAINTAINED IN A SILENCED STATE BUT NON-SPECIFIC ACTIVATION OF ERVS CAN OCCUR THROUGH APPLICATION OF EXOGENOUS STRESSORS AND MAY HAVE DETRIMENTAL CONSEQUENCES TO THE HOST. INDEED WITHIN THE LAST 5 YEARS A NUMBER OF STUDIES HAVE DEMONSTRATED ERVS TO BE ASSOCIATED WITH AUTOIMMUNE DISEASES CANCER AND NEUROLOGICAL DISEASES. EXTENDED SPACE TRAVEL WILL EXPOSE ASTRONAUTS TO THE SPACE RADIATION AND MICROGRAVITY ENVIRONMENTS BOTH OF THESE STRESSOR MAY INFLUENCE GENOMIC MODIFICATIONS THAT MAY RESULT IN NON-SPECIFIC ACTIVATION OF ERVS. ACTIVATION OF ERVS MAY RESULT IN ALTERATIONS TO MOLECULAR PATHWAYS WITHIN DIFFERENT CELL TYPES THAT MIGHT INFLUENCE NEGATIVE PATHOGENIC OUTCOMES DURING SPACE FLIGHT. THE KEY CENTRAL OBJECTIVE OF THIS PROPOSAL IS TO UNDERSTAND HOW THE PHYSICAL SPACE ENVIRONMENT MIGHT INFLUENCE ACTIVATION OF ERVS. WE WILL ACCOMPLISH THIS RESEARCH OBJECTIVE IN TWO AIMS. IN THE FIRST AIM WE WILL UTILIZE A BIOREACTOR TO GROW CELLS IN A MICROGRAVITY ENVIRONMENT AND EVALUATE THE CELLS BY MOLECULAR AND IMMUNOFLUORESCENCE TECHNIQUES FOR EVIDENCE OF ERV ACTIVATION UNDER THIS SPACE STRESSOR. THE SECOND AIM WILL UTILIZE AN ESTABLISHED TISSUE REPOSITORY THAT CONTAINS MULTIPLE TISSUES FROM MICE EXPOSED TO VARIOUS TYPES AND DOSES OF SPACE RADIATION. WE WILL EXAMINE THESE TISSUES MOLECULARLY AND HISTOLOGICALLY FOR EVIDENCE OF ERV ACTIVATION. THIS PROJECT IS SIGNIFICANT IN THAT IDENTIFICATION OF ERVS THAT RESPOND TO SPECIFIC SPACE CONDITIONS MAY FUNCTION AS EARLY SURROGATE MARKERS OF PUTATIVE GENOMIC CHANGE. FURTHERMORE EXPRESSION OF ERV-ENCODED PROTEINS MAY BE SEEN AS FOREIGN AND ELICIT AUTOIMMUNE RESPONSES. .