Project Grant R01HD114615

THE PHYSIOLOGICAL AND GENETIC BASIS OF GESTATIONAL ADAPTATIONS TO HYPOXIA - HYPOXIA IS A COMMON FEATURE OF GESTATIONAL COMPLICATIONS. EVEN WHEN THE ORIGINS OF HYPOXIA VARY (I.E., ENVIRONMENTAL HYPOXIA VERSUS HYPOXIA LIMITED TO THE PLACENTA), THERE ARE SHARED, INTERMEDIATE FEATURES IN PLACENTAL PHYSIOLOGY THAT ARE ALSO COMMON ACROSS MAMMALS. THESE COMMONALITIES SUGGEST THAT THERE ARE SOME FUNDAMENTAL EFFECTS OF HYPOXIA ON PLACENTAL DEVELOPMENT THAT NEGATIVELY IMPACT GESTATIONAL OUTCOMES. WE RECENTLY DEMONSTRATED THAT EVOLUTIONARY ADAPTATIONS TO CHRONIC HYPOXIA IN HIGH ELEVATION ENVIRONMENTS PROTECTS PLACENTAL AND FETAL GROWTH IN DEER MICE ACT ON MECHANISMS SHARED WITH HUMANS. THESE RESULTS POINT TO CONSERVED PROCESSES THAT ARE INVOLVED IN BOTH MEDIATING THE NEGATIVE IMPACTS OF HYPOXIA ON FETAL OUTCOMES AND PREVENTING THESE EFFECTS. IN THIS PROPOSAL, WE ADDRESS THREE KEY QUESTIONS, THE ANSWERS TO WHICH WILL SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF HOW PLACENTAL RESPONSES TO HYPOXIA CONTRIBUTE TO ADVERSE GESTATIONAL OUTCOMES (PARTICULARLY FETAL GROWTH RESTRICTION) AND THE GENETIC AND CELL TYPE-SPECIFIC MECHANISMS THAT UNDERLIE VARIATION IN SUSCEPTIBILITY TO THESE COMPLICATIONS. FIRST, WE ASK HOW INDIVIDUAL PLACENTAL CELL TYPE RESPONSES HYPOXIA CONTRIBUTE TO TISSUE-LEVEL OUTCOMES, INCLUDING IDENTIFYING THE CELL TYPES THAT ARE RESPONSIBLE FOR TISSUE-WIDE TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH FETAL GROWTH UNDER HYPOXIA. TO ANSWER THIS FIRST QUESTION, WE GENERATE CELL TYPE-SPECIFIC TRANSCRIPTOMES FROM PLACENTAL TISSUES USING SINGLE-NUCLEI RNASEQ FROM HIGHLAND-ADAPTED AND NON-ADAPTED MICE EXPERIMENTALLY ACCLIMATED DURING GESTATION TO HYPOXIA OR NORMOXIA. SECOND, WE INTERROGATE THE CIS-REGULATORY VARIATION THAT EXPLAINS CELL TYPE-SPECIFIC TRANSCRIPTIONAL VARIATION BY LINKING ALLELE-SPECIFIC GENE EXPRESSION TO CHROMATIN CONFORMATION IN PLACENTAS FROM F1 HYBRID CROSSES OF THE AFOREMENTIONED POPULATIONS, AGAIN IN AN EXPERIMENTAL FRAMEWORK. FINALLY, OUR THIRD AIM ASKS HOW THESE CELL TYPE-SPECIFIC HYPOXIA RESPONSES CONTRIBUTE TO ORGANIZATIONAL REMODELING OF THE PLACENTAL EXCHANGE STRUCTURES BY COMBINING IN VIVO HISTOLOGICAL APPROACHES AND IN VITRO EXPERIMENTAL APPROACHES FOCUSED ON CELL-AUTONOMOUS FUNCTION OF A SINGLE, IMPORTANT PLACENTAL CELL TYPE. THE PROPOSED AIMS THUS COMBINE EXPERIMENTAL APPROACHES, CUTTING-EDGE SEQUENCING ANALYSES, AND MOLECULAR AND CELLULAR BIOLOGY WITH THE BROADER GOAL OF RESOLVING THE GENETIC AND DEVELOPMENTAL PROCESSES BY WHICH NATURAL GENETIC VARIATION ALTERS PLACENTAL FUNCTION AND INFLUENCES FETAL OUTCOMES. THE RESULTS OF THIS RESEARCH WILL ADVANCE OUR UNDERSTANDING OF CONSERVED PHYSIOLOGY THAT SHAPES PLACENTAL DEVELOPMENT AND PREGNANCY IN MAMMALS, THEREBY SUPPORTING BROADER RESEARCH FOCUSED ON GESTATIONAL HEALTH AND DISEASE IN HUMANS.