INFERTILITY AND SUBFERTILITY ARE PREVALENT PROBLEMS IN DOMESTIC ANIMALS AND HUMANS. OUR BROAD, LONG-TERM OBJECTIVE IS TO DISCOVER AND UNDERSTAND KEY PHYSIOLOGICAL PATHWAYS REGULATING DEVELOPMENT AND FUNCTION OF THE UTERUS AND CONCEPTUS (EMBRYO/FETUS AND ASSOCIATED EXTRAEMBRYONIC MEMBRANES) IN ORDER TO PROVIDE FUNDAMENTAL INFORMATION USEFUL FOR DIAGNOSIS, PREVENTION AND TREATMENT OF FERTILITY PROBLEMS IN DOMESTIC ANIMALS AND HUMANS. THE RECEPTIVE UTERUS REPRESENTS A TEMPORARY, BUT UNIQUE PHYSIOLOGICAL STATE WHEN CONCEPTUS DEVELOPMENT AND IMPLANTATION IS POSSIBLE. INADEQUATE UTERINE RECEPTIVITY AND CONCEPTUS-MATERNAL INTERACTIONS NEGATIVELY AFFECTS CONCEPTUS DEVELOPMENT, SIGNALING FOR PREGNANCY RECOGNITION, IMPLANTATION AND ESTABLISHMENT OF PREGNANCY. DEFECTS IN THOSE CRITICAL BIOLOGICAL PROCESSES ARE CONSIDERED PRIMARY CAUSES OF PREGNANCY LOSS AND MAY BE THE ORIGIN OF LATER PREGNANCY COMPLICATIONS IN BOTH DOMESTIC ANIMALS AND HUMANS. THE GOAL OF THIS PROPOSAL IS TO INVESTIGATE THE IDEATHAT EXTRACELLULAR VESICLES REPRESENT A NEW PARADIGM IN UTERINE RECEPTIVITY AND CONCEPTUS-MATERNAL INTERACTIONS AND HAVE A BIOLOGICAL ROLE IN PREGNANCY. EXOSOMES/MICROVESICLES ARE NANO-SIZED, CELL-DERIVED VESICLES THAT MEDIATE CELL-CELL COMMUNICATION BY ENTERING TARGET CELLS AND ELICITING BIOLOGICAL EFFECTS VIA GENE REGULATION AND ALTERATION OF CELLULAR PATHWAYS IMPACTING CELL SURVIVAL AND GROWTH. OUR CENTRAL HYPOTHESIS IS THAT EXOSOMES/MICROVESICLES, EMANATING FROM THE UTERUS AND CONCEPTUS, ARE IMPORTANT FUNCTIONAL MEDIATORS OF UTERINE RECEPTIVITY, CONCEPTUS-MATERNAL INTERACTIONS, AND CONCEPTUS DEVELOPMENT AND IMPLANTATION. SPECIFIC AIMS ARE TO: (1) UNDERSTAND EXOSOMES/MICROVESICLES IN THE UTERUS DURING EARLY PREGNANCY; AND (2) DETERMINE FUNCTIONAL ROLE OF EXOSOMES/MICROVESICLES AND UTERINE LUMINAL FLUID IN CONCEPTUS DEVELOPMENT. THIS RESEARCH IS INNOVATIVE, BECAUSE IT TAKES ADVANTAGE OF: (A) THE UTERINE GLAND KNOCKOUT (UGKO) SHEEP MODEL THAT EXHIBITS RECURRENT PREGNANCY LOSS; (B) ABILITY TO CONDUCT FUNCTIONAL STUDIES IN SHEEP AS A MODEL RUMINANT; AND (C) RECENT ADVANCES IN HIGH-THROUGHPUT GENOMICS AND PROTEOMICS ANALYSES AND KNOWLEDGE OF RUMINANT GENOMES. COMPLETION OF THE RESEARCH IS EXPECTED TO FILL A SUBSTANTIAL GAP IN OUR EXISTING KNOWLEDGE OF EXOSOME/MICROVESICLE BIOLOGY AND BIOLOGICAL PATHWAYS GOVERNING EARLY PREGNANCY SUCCESS AND LOSS. TRANSLATIONAL OUTCOMES OF THE RESEARCH INCLUDE BIOMARKERS AND SELECTION TOOLS OF UTERINE RECEPTIVITY AND HEALTHY CONCEPTUS-MATERNAL INTERACTIONS, WHICH CAN BE USED TO IMPROVE NATURAL AND ASSISTED REPRODUCTION IN BOTH DOMESTIC RUMINANTS AND HUMANS. THUS, THE RESEARCH HAS A DUAL BENEFIT FOR THE IMPROVEMENT OF HUMAN HEALTH AND AN INCREASE IN FOOD ANIMAL PRODUCTION.