Project Grant F31HD123818

INVESTIGATING THE PLACENTAL SELENOPROTEOME - PROJECT SUMMARY/ABSTRACT SELENIUM (SE) IS AN ESSENTIAL TRACE ELEMENT REQUIRED FOR A HEALTHY PREGNANCY, AND IT HAS BEEN ESTIMATED THAT 2.8 BILLION PEOPLE WORLDWIDE DO NOT CONSUME ENOUGH SE. MATERNAL SE DEFICIENCY IS ASSOCIATED WITH MISCARRIAGE, INFERTILITY, PRETERM BIRTH, FETAL GROWTH RESTRICTION (FGR), PLACENTAL DYSFUNCTION, GESTATIONAL DIABETES MELLITUS, AND PREECLAMPSIA. SE IS INCORPORATED INTO SELENOPROTEINS FOR FUNCTION. SELENOPROTEINS ARE PRODUCED BY THE PLACENTA AND ARE CRITICAL FOR CELLULAR METABOLISM AND MITIGATION OF OXIDATIVE STRESS. THE PLACENTA IS A HIGHLY METABOLIC ORGAN WHOSE GROWTH AND FUNCTION ARE REQUIRED FOR PROPER FETAL DEVELOPMENT. METABOLIC DYSREGULATION CAN LEAD TO THE ACCUMULATION OF REACTIVE OXYGEN SPECIES AND COMPROMISE FUNCTION. DESPITE THE WELL-ESTABLISHED INVOLVEMENT OF SE AND SELENOPROTEINS IN THESE PROCESSES AND THE LINKS BETWEEN ADVERSE PREGNANCY OUTCOMES AND SE DEFICIENCY, THERE HAS BEEN NO INVESTIGATION WHICH TRULY OUTLINES THE FUNCTIONAL SIGNIFICANCE OF SELENOPROTEINS PRODUCED BY THE PLACENTA. THESE INCLUDE IODOTHYRONINE DEIODINASE 2 (DIO2), A SELENOPROTEIN RESPONSIBLE FOR THYROID HORMONE METABOLISM, WHICH IS INDISPENSABLE FOR HUMANS. MOREOVER, A RATE-LIMITING FACTOR OF SELENOPROTEIN BIOSYNTHESIS, SECIS BINDING PROTEIN 2 (SBP2), IS ALSO PRODUCED BY THE PLACENTA. SBP2 MUTATIONS MANIFEST IN ADULT INFERTILITY AND SIGNIFICANTLY IMPACTED GROWTH AND ABNORMAL THYROID HORMONE PROFILES. THE OBJECTIVE OF THIS F31 PREDOCTORAL FELLOWSHIP IS TO USE OUR IN VIVO PLACENTA-SPECIFIC LENTIVIRAL-MEDIATED RNA INTERFERENCE (RNAI) TECHNIQUE TO DIRECTLY INVESTIGATE THE ROLE OF THE PLACENTAL SELENOPROTEOME DURING THE FIRST HALF OF GESTATION USING THE SHEEP MODEL. AIM 1 WILL TEST THE HYPOTHESIS THAT PLACENTAL DIO2 DEFICIENCY RESULTS IN PLACENTAL INSUFFICIENCY AND ABNORMAL THYROID HORMONE METABOLISM IN SHEEP AT MIDGESTATION [75 DAYS OF GESTATIONAL AGE (DGA)]. AIM 2 WILL TEST THE HYPOTHESIS THAT PLACENTAL SBP2 DEFICIENCY WILL RESULT IN A DECREASED PLACENTAL SELENOPROTEOME, LEADING TO PLACENTAL METABOLIC DYSFUNCTION AND OXIDATIVE STRESS, WITH ABERRANT PLACENTAL DEVELOPMENT AND SIGNIFICANT FGR RESULTING AS CONSEQUENCE AT MIDGESTATION (75 DGA). THESE PROJECTS WILL BE THE FIRST TO DIRECTLY IDENTIFY THE ROLE OF PLACENTAL SELENOPROTEINS IN PREGNANCY. ALL WORK WILL BE COMPLETED AT THE ANIMAL REPRODUCTION AND BIOTECHNOLOGY LABORATORY AT COLORADO STATE UNIVERSITY AND OVERSEEN BY MY SUPPORTIVE SPONSOR, DR. QUINTON WINGER, AND CO-SPONSOR, DR. JANE STREMMING, WHO RESIDES AT THE UNIVERSITY OF COLORADO ANSCHUTZ MEDICAL CAMPUS. MY TAILORED TRAINING PLAN IS DESIGNED TO SUPPORT MY DEVELOPMENT INTO A WELL-ROUNDED, INDEPENDENT BIOMEDICAL SCIENTIST. IT WILL EMPHASIZE MY ADVANCEMENTS IN SCIENTIFIC COMMUNICATION AND GRANTSMANSHIP, SURGICAL AND LEADERSHIP SKILLS, AND OVERALL UNDERSTANDING OF PLACENTAL AND FETAL PHYSIOLOGY AS PREGNANCY PROGRESSES. OUR LONG-TERM GOAL IS TO UNDERSTAND HOW THE PLACENTAL SELENOPROTEOME CONTRIBUTES TO PREGNANCY OUTCOMES. THIS PROPOSAL DIRECTLY ADDRESSES THE NICHD'S RESEARCH GOAL 3: "SETTING THE FOUNDATION FOR HEALTHY PREGNANCIES AND LIFELONG WELLNESS" THROUGH THE USE OF INNOVATIVE BASIC AND TRANSLATIONAL SCIENCE APPROACHES TO FURTHER UNDERSTAND IMPACTS ON THE PLACENTA AND ITS RESULTING FETAL IMPACTS IN GESTATION.