**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** A MAJOR NEGATIVE CAVEAT OF GLOBAL CLIMATE CHANGE IS HEAT STRESS AND ITS IMPAIRMENTS ON REPRODUCTION IN HUMANS AND ANIMALS. IN CATTLE, MATERNAL HYPERTHERMIA INDUCED THROUGH ENVIRONMENTAL RISES IN TEMPERATURE NEGATIVELY IMPACTS CELLULAR AND MOLECULAR FUNCTION LEADING TO IMPAIRED FERTILIZATION AND EMBRYO DEVELOPMENT, CONFOUNDING THE ETIOLOGY OF HYPERTHERMIA-INDUCED INFERTILITY. EXTRACELLULAR VESICLES (EVS), WHICH ARE CELL-SECRETED NANOPARTICLES ARE MORE RECENTLY KNOWN FOR THEIR ROLE AS CARGO CARRIES OF BIOACTIVE CONSTITUENTS (RNAS & PROTEINS) REGULATING CELLULAR BIDIRECTIONAL COMMUNICATION. WHILE WE KNOW THAT EVS RELEASED IN RESPONSE TO HEAT STRESS HAVE THE CAPACITY TO INDUCE BYSTANDER PROTECTION AGAINST RECURRENT STRESS, THE MOLECULAR CARGOES RESPONSIBLE FOR THIS RESPONSE ARE LARGELY UNKNOWN. TO ADDRESS SUCH FUNCTIONAL ALTERATIONS AT THE CELLULAR LEVEL, WE IDENTIFIED TWO KEY UPREGULATED MIRNA (BTA-MIR-1246 & BTA-MIR-2904) ENCAPSULATED WITHIN EVS RELEASED FROM STRESSED GRANULOSA CELLS COMPARED TO THOSE FROM CONTROL CELLS. GIVEN THE REGULATORY FUNCTIONAL SIGNIFICANCE OF MIRNAS, OUR LABORATORIES MAIN FOCUS IS TO ELUCIDATE THE FUNCTION OF THE SPECIFIED MIRNAS THROUGH ENDOGENOUS AND EXOGENOUS LOADING MEASURES INTO CONTROL EVS TO MIMIC THE MIRNA CONTENT OF STRESSED EVS. THE CENTRAL HYPOTHESIS OF THIS APPLICATION IS THAT STRESS-ASSOCIATED MIRNAS LOADED INTO CONTROL EVS CAN MIMIC THE FUNCTION OF STRESSED EVS FOLLOWING TRANSFER TO RECIPIENT FOLLICULAR CELLS AND OOCYTES, WHEREBY OFFSETTING THE DETRIMENTAL EFFECTS OF HEAT STRESS, PROMOTING THERMOTOLERANCE TO RECURRENT STRESS. WHILE EV RESEARCH IS STILL LARGELY IN ITS INFANCY, LONG-TERM THE NOVELTY AND INNOVATIVE NATURE OF THE PROPOSED WORK CAN PROVIDE INSIGHT TO EV-MEDIATED MOLECULAR SIGNALING IN MAMMALIAN REPRODUCTION.

Colorado State University, Fort Collins CO

Investigators