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

利用自然适应推动高原相关产科并发症的治疗创新

• 批准号: 10473514
• 负责人: Kathryn Wilsterman
• 金额: $ 0.85万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473514
• 关键词: Academic skills; Adult; Adverse effects; Altitude; Andean; Automobile Driving; Biological Models; Birth; Chinese; Chronic; Clinical; Data; Deer; Deer Mouse; Development; Discipline of obstetrics; Disease; Environmental Risk Factor; Etiology; European; Evolution; Fellowship; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal health; Foundations; Gene Expression Profile; Genes; Genomic approach; Genomics; Goals; Growth; Health; Histologic; Human; Hypoxia; Immunohistochemistry; Indigenous; Individual; Infant Health; Infrastructure; Intervention; Kansas; Laboratory mice; Life; Mammals; Maternal Health; Measures; Medical; Modeling; Molecular; Montana; Morphology; Mothers; Mouse Strains; Outcome; Pathologic; Pathway interactions; Peromyscus; Phenotype; Physiological; Physiology; Placenta; Placentation; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Preventive treatment; Process; Research; Resistance; Risk; Rodent; Shapes; Structure; System; Testing; Time; Tissues; Training; Universities; Variant; Vascular remodeling; Woman; Work; base; experience; experimental study; fetal; functional genomics; functional plasticity; gene network; gestational hypoxia; implantation; improved; innovation; insight; novel; obstetrical complication; preservation; prevent; pup; residence; response; theories; therapy development; trait; transcriptome; transcriptome sequencing; transcriptomics

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.

在高海拔地区（> 2500米）怀孕的3-4倍更有可能涉及并发症，如宫内生长受限和先兆子痫，这可能对孕产妇和婴儿的健康产生长期影响。然而，土著安第斯人和西藏人，谁是土生土长的高海拔地区，没有经历这些并发症的风险增加。了解保护高原适应人群中胎儿发育和孕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，以改善高原妊娠结局。我建议使用一个新兴的模型系统的高度适应，鹿鼠（Peromyscus maniculatus），以确定病理胎盘在海拔高度和进化适应，允许正常的胎儿生长在海拔高度的过程。和人类一样，低地鹿鼠在模拟海拔下经历胎儿生长限制，而适应海拔的鹿鼠能够保持正常的胎儿生长。此外，胎盘适应似乎参与了高原人的胎儿生长保护。为了了解低压缺氧和高原适应如何塑造胎盘和胎盘功能，我将结合联合收割机功能基因组分析胎盘组织在三个妊娠时间点的胎盘和胎儿发育的组织学和形态学措施，从低地和高原鹿小鼠在低压缺氧下怀孕。我还将在我的实验中包括一个远系繁殖的实验室小鼠品系，以确定保守的胎盘对缺氧的反应。首先，我将区分适应性和适应不良的结构可塑性胎盘在海拔高度使用免疫组织化学。第二，我将使用RNASeq从胎盘中生成层特异性转录组，以鉴定塑料胎盘形成的基因网络和稳定性。提出的目标将促进我们对高海拔胎盘形成及其对胎儿健康影响的理解，并通过识别进化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，该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，以促进整个奖学金任期内专业和学术技能的全面发展。合作者堪萨斯大学的Soares博士将提供针对胎盘形成和缺氧的额外知识和技术培训。

项目成果

Evolution in reproductive tempo and investment across the Peromyscus radiation.

• DOI: 10.1002/jez.2666
• 发表时间: 2023-01
• 期刊: JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY
• 影响因子: 2.8
• 作者: Wilsterman, Kathryn;Cunningham, Kirksey
• 通讯作者: Cunningham, Kirksey