权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结