IN THE UNITED STATES, INCOME FROM FARM ANIMALS AND FEED CROPS IS NEARLY $200 BILLION PER YEAR, WITH OVER 40% OF GRAIN CROPS BEING USED FOR FEED. MOREOVER, FARM ANIMALS AND THEIR PRODUCTS PROVIDE AN IMPORTANT SOURCE OF HIGH QUALITY FOOD FOR HUMAN CONSUMPTION AND ALSO ARE CRITICAL FOR SUSTAINABLE FARMING SYSTEMS. THE PROPOSED STUDIES ARE AIMED AT ADDRESSING SIGNIFICANT GAPS IN OUR UNDERSTANDING OF THE PHYSIOLOGY OF PARTURITION THAT DIRECTLY IMPACTS THE HIGH RATE (APPROXIMATELY 10%) OF NEWBORN MORTALITY SEEN ACROSS SEVERAL LIVESTOCK SPECIES. STEROID PRODUCTION IS REQUIRED BOTH FOR SUCCESSFUL PREGNANCY AND THE DELIVERY OF HEALTHY OFFSPRING IN MAMMALS. PREGNANCY IN MOST SPECIES IS RELIANT ON CONTINUED SUPPORT BY PROGESTERONE, EITHER FROM FUNCTIONALLY ACTIVE OVARIAN LUTEAL TISSUE OR, LATER IN PREGNANCY IN SPECIES LIKE SHEEP AND HORSE, FROM THE PLACENTA. CONVERSELY, THE BIRTH PROCESS DEPENDS ON PHYSIOLOGICAL PROGESTERONE WITHDRAWAL RESULTING FROM ONE OF SEVERAL POSSIBLE MECHANISMS INCLUDINGA DECREASE IN OVARIAN OR PLACENTAL PROGESTERONE PRODUCTION, OR A DECLINE IN THE RESPONSES OF THE UTERUS TO PROGESTERONE DUE TO DECREASED PROGESTERONE RECEPTOR SIGNALING (IE "FUNCTIONAL" WITHDRAWAL). LONG-TERM GOAL: THE LONG-TERM GOAL OF THIS PROJECT IS TO BETTER UNDERSTAND THE MECHANISMS OF DELIVERY AND FETAL MATURATION, LEADING TO BIRTH OF A HEALTHY, VIABLE OFFSPRING. THE PROPOSED STUDIES WILL DETERMINE THE INVOLVEMENT OF TWO RELATIVELY UNEXPLORED SYSTEMS, NAMELY (1) THE ROLE OF SO-CALLED NEUROSTEROIDS IN SUPPRESSING ACTIVATION OF THE FETAL HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WHICH REGULATES NOT ONLY THE TIMING OF DELIVERY BUT ALSO MATURAITON OF FETAL ORGANS (FOR EXAMPLE THE FETAL LUNG), AND (2) THE DIRECT EFFECTS OF ESTROGENS IN THE INITIATION OF PARTURITION. TO ADDRESS THESE ISSUES, WE PROPOSE THE FOLLOWING THREE SPECIFIC AIMS:· AIM 1 - DETERMINE THE INFLUENCE OF NEUROSTEROIDS IN THE ACTIVATION AND/OR SUPPRESSION OF THE FETAL HPA AXIS AND THUS IN THE FETAL PREPARATION FOR PARTURITION.· AIM 2 - DETERMINE THE ACUTE AND LONGER-TERM EFFECTS FETAL NEUROSTEROID ADMINISTRATION ON ACTIVATION OF THE FETAL HPA AXIS, INDUCTION OF PARTURITION, AND FETAL ORGAN MATURATION.· AIM 3 - DETERMINE THE DIRECT EFFECT OF ESTROGEN ON MATERNAL AND FETAL TISSUE RESPONSES AND MECHANISMS OF PARTURITION. THE RESULTS OF THESE STUDIES WILL ESTABLISH THE ROLE OF RELATIVELY UNEXPLORED AND UNDEFINED STEROID PATHWAYS IN FETAL MATURATION AND INITIATION OF DELIVERY, THEREBY SUGGESTING NOVEL MANAGEMENT STRATEGIES OR NEW THERAPEUTIC TARGETS, WHICH CAN BE USED TO REDUCE POSTNATAL MORTALITY IN LIVESTOCK, WHICH IS A PROBLEM OF NATIONAL SIGNIFICANCE.

North Dakota State University, Fargo ND

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