Understanding the etiology of altitude-related obstetric complications through evolutionary adaptation

项目摘要 在高海拔地区（> 2500米）怀孕，并发症的可能性是其他地区的3-4倍（胎儿生长受限， 先兆子痫等），这对产妇和婴儿的健康有长期影响。然而，土著人 安第斯人和西藏人，谁是土生土长的高海拔地区，没有经验的风险增加，这些并发症 在高空。了解保护胎儿发育和母体的潜在生理机制 适应海拔人群的健康状况可能导致临床干预或预防性治疗， 怀孕期间的高海拔妇女。然而，在这方面取得的进展有限， 在伦理和逻辑上都是对人类研究的挑战。我们建议使用一个新兴的模型系统 对于高原适应，鹿鼠（Peromyscus maniculatus），回答这些基本问题， 妊娠进展和健康。与人类一样，高地鹿鼠也表现出对海拔高度的生殖适应性 而低地对应物在模拟海拔高度下经历升高的后代死亡率。我们将联合收割机 在三个关键的妊娠时间点用组织学对胎盘组织进行功能基因组分析， 胎盘和胎儿发育的形态学测量，以产生最全面的分析， 胎盘形成和胎盘功能。我们将使用比较生理学 通过比较来自这些地点的低地和高地的常氧和低氧暴露的鹿鼠， 在相同条件下，将时间点与远交实验室小鼠品系进行比较，以确定对 缺氧保护高原胎盘形成和保守的胎盘对缺氧的反应是病理学的基础。 首先，我们将量化胎盘发育和结构中HH依赖的可塑性， 非适应鹿鼠种群使用组织学方法。这些数据将使我们能够评估 胎盘特性的可塑性是适应性的还是不适应性的。第二，我们将产生 转录组（通过RNAseq）和甲基化组（通过还原亚硫酸氢盐测序[RRBS]）， 胎盘的两个主要功能层中的每一层，并使用功能基因组学的分析方法， 了解基因表达的调节如何成为胎盘表型的基础。这些分析将 帮助我们了解基因如何在海拔适应人群中进行选择有助于调节 和胎盘形成的基因网络结构。拟议的目标将在以下方面取得重大进展 了解胎盘如何发育和影响胎儿健康，他们将提供新的方向 通过识别进化已经适应性改变的途径进行医疗干预。拟议项目将 支持学生接触尖端的生物医学研究，同时加强研究环境 通过新技术的建立以及与蒙大拿大学正在进行的工作的协同作用。

PROJECT SUMMARY Pregnancies at high altitude (>2500m) are 3-4 times more likely to involve complications (fetal growth restriction, pre-eclampsia, etc.), which have long-term repercussions 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 at altitude. Understanding the underlying physiological mechanisms that protect fetal development and maternal health in altitude-adapted populations could lead to clinical interventions or preventative treatments to protect women at altitude during pregnancy. However, limited progress has been made on this front because pregnancy is both ethically and logistically challenging to study in humans. We propose to use an emerging model system for altitude adaptation, the deer mouse (Peromyscus maniculatus), to answer these fundamental questions about pregnancy progression and health. As in humans, highland deer mice display reproductive adaptations to altitude whereas lowland counterparts experience elevated offspring mortality under simulated altitude. We will combine functional genomic analysis of placenta tissue at three critical gestational time-points with histology and morphological measures of placental and fetal development to generate the most comprehensive analysis of placentation and placental function under simulated hypoxia to-date. We will use a comparative physiology approach by comparing normoxia- and hypoxia-exposed deer mice from lowland and highland sites at these timepoints to outbred laboratory mouse strains under the same conditions to identify both adaptive response to hypoxia that protect highland placentation and conserved, placental responses to hypoxia that underly pathology. First, we will quantify HH-dependent plasticity in placental development and structure in altitude-adapted and non-adapted deer mouse populations using histological approaches. These data will allow us to evaluate whether plasticity in a given placenta trait is likely to be adaptive or maladaptive. Second, we will generate transcriptomes (via RNAseq) and methylomes (via reduced representation bisulfite sequencing [RRBS]) from each of the two major functional layers of the placenta and use analytical approaches from functional genomics to understand how regulation of gene expression underlies placental phenotypes. Together, these analyses will help us to understand how genes undergoing selection in altitude-adapted populations contribute to regulation and structure of gene networks underlying placentation. The proposed aims will produce major advances in understanding how the placenta develops and affects fetal health, and they will provide new directions for medical intervention by identifying pathways that evolution has adaptively altered. The proposed project will support student exposure to cutting-edge biomedical research while strengthening the research environment through new technique establishment and synergy with on-going work at the University of Montana.