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

通过进化适应了解海拔相关产科并发症的病因

基本信息

批准号：
10046697
负责人：
Zachary Cheviron
金额：
$ 44.07万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046697
关键词：
Affect Altitude Andean Biological Models Biomedical Research Cardiovascular Diseases Child Chronic Clinical Comparative Physiology Data Deer Mouse Development Discipline of obstetrics Disease Environment Ethics Etiology Evolution Exposure to Faculty Family Fetal Development Fetal Growth Fetal Growth Retardation Fetal health Foundations Gene Expression Gene Expression Regulation Genes Genomic approach Genomics Growth Health Histologic Histology Human Hypoxia Indigenous Infant Health Intervention Laboratories Laboratory mice Lead Life Logistics Low Birth Weight Infant Lung diseases Mammals Maternal Health Measures Medical Methylation Molecular Montana Morphology Mothers Mouse Strains Mus Pathology Pathway interactions Peromyscus Phenotype Physiological Physiology Placenta Placentation Population Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Preventive treatment Regulation Research Risk Rodent Rural Site Structure Students Techniques Testing Time Tissue-Specific Gene Expression Tissues Underrepresented Students Universities Vascular remodeling Woman Work bisulfite bisulfite sequencing experience functional genomics functional plasticity graduate student higher education innovation insight methylome mortality novel obstetrical complication offspring preservation pup reproductive residence response stem student training synergism theories therapy development trait transcriptome transcriptome sequencing undergraduate student virtual

项目摘要

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.

项目摘要高海拔（> 2500m）的怀孕涉及并发症的可能性高3-4倍（胎儿生长限制， explampsia等），对孕产妇和婴儿健康产生长期影响。但是，土著本地高海拔的安第斯和藏人不会出现这些并发症的风险升高在高度。了解保护胎儿发育和母体的潜在生理机制适应高度的人群的健康可能会导致临床干预措施或预防治疗以保护怀孕期间海拔高度的妇女。但是，由于怀孕，在这方面取得了有限的进展在道德上和逻辑上都具有挑战性地学习人类。我们建议使用新兴模型系统为了适应高度，鹿鼠（peromyscus maniculatus）回答了这些基本问题怀孕进展和健康。就像在人类中一样，高地鹿小鼠表现出生殖适应高度而低地同行在模拟高度下经历了后代死亡率升高。我们将结合在三个关键的妊娠时间点，具有组织学和的功能性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在模拟的缺氧及时下的胎盘功能和胎盘功能。我们将使用比较生理学通过比较来自低地和高地位点的正氧和低氧鹿小鼠的方法在相同条件下的近代实验室小鼠菌株的时间点，以确定对保护高地胎盘和保守的胎盘反应的缺氧对低氧的胎盘反应。首先，我们将在适应高度的胎盘发育和结构中量化HH依赖性可塑性使用组织学方法的非适应性鹿小鼠种群。这些数据将使我们能够评估在给定的胎盘性状中的可塑性是否可能是适应性的还是适应不良的。第二，我们将生成转录组（通过RNASEQ）和甲基组（通过减少表示硫酸盐测序[RRBS]）胎盘的两个主要功能层中的每一个，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构成胎盘表型的基础。这些分析将在一起帮助我们了解在适应高度的人群中选择的基因如何有助于调节和基因网络的结构。拟议的目标将在了解胎盘如何发展和影响胎儿健康，它们将为通过确定进化的途径已适应改变，医疗干预措施。拟议的项目将支持学生对尖端生物医学研究的接触，同时加强研究环境通过新技术建立和协同作用，在蒙大拿大学的持续工作中进行。