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

在海拔2500米的高海拔地区怀孕，发生并发症的可能性要高出3-4倍，如宫内生长受限和先兆子痫，这可能会对母婴健康产生长期影响。然而，原住在高海拔地区的安第斯人和藏族人并不会增加这些并发症的风险。了解在高原适应人群中保护胎儿发育和产妇健康的生理机制有助于确定临床干预或预防性治疗的目标，以改善高原地区的妊娠结局。我建议使用一种新兴的高原适应模型系统，鹿鼠(Permyscus Manulatus)，以确定高原病理性胎盘形成的潜在过程，以及允许胎儿在高原正常发育的进化适应。与人类一样，低地鹿鼠在模拟海拔条件下胎儿生长受限，而适应海拔的鹿鼠能够维持正常的胎儿生长。此外，在高地居民中，胎盘适应似乎与胎儿生长保护有关。为了了解低压缺氧和高原适应如何塑造胎盘和胎盘功能，我将结合对三个妊娠时间点的胎盘组织的功能基因组分析，以及在低压缺氧下怀孕的低地和高原鹿小鼠胎盘和胎儿发育的组织学和形态学测量。我还将在我的实验中包括一个外种的实验室小鼠品系，以确定保守的胎盘对低氧的反应。首先，我将用免疫组织化学方法区分高原胎盘的适应性和非适应性结构可塑性。其次，我将使用RNAseq从胎盘中产生特定于层的转录本，以确定塑料胎盘形成背后的基因网络和稳定性。提出的目标将促进我们对高原胎盘及其对胎儿健康影响的理解，并将通过确定进化已适应性改变的途径，为医学干预提供新的方向。拟议的研究将在蒙大拿大学的CHEVIRON和GOOD实验室完成，这些实验室提供与该项目相关的免费专业知识。CHEVIRON和Good实验室还通过蒙大拿大学拥有必要的经验和基础设施，以促进在整个奖学金终身教职期间专业和学术技能的全面发展。合作伙伴堪萨斯大学的苏亚雷斯博士将提供专门针对胎盘形成和缺氧的额外智力和技术培训。

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.