Using natural adaptation to drive treatment innovation for altitude-related obstetric complications

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Pregnancies at high altitude (>2500m) are 3–4 times more likely to involve complications, like intrauterine growth restriction and pre-eclampsia, that can have long-term impacts on maternal and infant health. However, indigenous Andeans and Tibetans, who are native to high altitude, do not experience an elevated risk for these complications. Understanding the physiological mechanisms that protect fetal development and maternal health in altitude-adapted populations could help identify targets for clinical intervention or preventative treatment to improve gestational outcomes at altitude. I propose to use an emerging model system for altitude adaptation, the deer mouse (Peromyscus maniculatus), to identify the processes underlying pathological placentation at altitude and the evolutionary adaptations that allow for normal fetal growth at altitude. As in humans, lowland deer mice experience fetal growth restriction under simulated altitude, whereas altitude- adapted deer mice are able to maintain normal fetal growth. In addition, placental adaptations appear to be involved in fetal growth preservation in highlanders. To understand how hypobaric hypoxia and altitude adaptation shape placentation and placental function, I will combine functional genomic analysis of placenta tissue across three gestational time-points with histological and morphological measures of placental and fetal development from lowland and highland deer mice gestating under hypobaric hypoxia. I will also include an outbred laboratory mouse strain in my experiments to identify conserved, placental responses to hypoxia. First, I will differentiate between adaptive and maladaptive structural plasticity in the placenta at altitude using immunohistochemistry. Second, I will generate layer-specific transcriptomes from placentas using RNASeq to identify gene networks and stability therein underlying plastic placentation. The proposed aims will advance our understanding of placentation at altitude and its effects on fetal health, and they will provide new directions for medical intervention by identifying pathways that evolution has adaptively altered. The proposed research will be completed in the Cheviron and Good labs at the University of Montana, which offer complimentary expertise relevant to this project. The Cheviron and Good labs also have the necessary experience and infrastructure through University of Montana to facilitate the comprehensive development of professional and academic skills across the fellowship tenure. Collaborator Dr. Soares at University of Kansas will provide additional intellectual and technical training specific to placentation and hypoxia.