Genomic and physiological mechanisms of hypoxia adaptation in high-altitude mice

高原小鼠缺氧适应的基因组和生理机制

基本信息

批准号：
10689032
负责人：
Jay Storz
金额：
$ 46.8万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689032
关键词：
ATP Synthesis Pathway Acclimatization Aerobic Aerobic Exercise Altitude American Andean Animals Biological Blood gas Candidate Disease Gene Cardiovascular system Catheters Chronic Comparative Study Complement Complex Consumption DNA Resequencing Deer Mouse Disease Down-Regulation Ear Evolution Exercise Experimental Designs Feedback Gene Expression Genes Genetic Genetic Crosses Genetic Polymorphism Genetic Transcription Genome Scan Genomics Genotype Goals Human Hypoxia Hypoxia Pathway Mammals Measures Mediating Metabolic Mitochondria Mus Muscle Nucleotides Operative Surgical Procedures Organ Outcome Oxygen Pathway interactions Patients Performance Peromyscus Phenotype Physiological Physiological Adaptation Physiology Plant Leaves Population Research Research Project Grants Resistance Rodent Sampling Sea South American Structure System Testing Tissue-Specific Gene Expression Tissues Translating Up-Regulation VO2max Variant Venous Work deprivation design exercise capacity experimental study follow-up functional genomics gene function gene network human subject in vivo insight instrumentation metabolomics novel novel therapeutic intervention programs respiratory response stem trait transcription factor transcriptomics

项目摘要

PROJECT SUMMARY High-altitude animals have evolved the ability to survive and function under conditions of oxygen deprivation (hypoxia) that mimic disease states in humans. Identifying evolved mechanisms of hypoxia adaptation in mammals that are long-term high-altitude natives can therefore yield discoveries of biomedical relevance while also providing general insights into the evolution of complex traits. A number of wild rodent species inhabit far more extreme altitudes than Tibetan and Andean humans and also represent far more tractable subjects for experimental approaches that involve genetic crosses and invasive physiological manipulations. This project integrates genomics and experimental physiology to dissect the mechanistic basis of adaptive enhancements of whole-animal performance in hypoxia in extreme high-altitude rodents. The experiments compare high- and low- altitude populations of two species: the deer mouse (Peromyscus maniculatus), which has the broadest altitudinal range of any North American mammal (sea level to 4350 m), and the Andean leaf-eared mouse (Phyllotis vaccarum), an extremophile species that holds the record as the world’s highest dwelling mammal and that also has the broadest altitudinal range (sea level to >6700 m [>22,000’]). To test hypotheses about adaptive regulatory responses to hypoxia, we will use a common-garden experimental design to integrate measures of whole-animal physiological performance (aerobic exercise capacity in hypoxia) and various subordinate traits (respiratory, cardiovascular, and metabolic) with tissue-specific transcriptomic and metabolomic profiles. Experiments will involve highly invasive manipulations (e.g., surgical instrumentation of arterial and venous catheters to measure blood gases during exercise trials and terminal sampling of vital organs) that are not feasible in human subjects. In both species, mechanistic experiments will be complemented by population genomic experiments to generate hypotheses about the specific genes and pathways that may have contributed to hypoxia adaptation. Such hypotheses will then be tested using follow-up experiments to measure phenotypic effects of changes in gene function and/or gene expression, as illustrated by our ongoing work on deer mice. The specific aims of the research are (1) to elucidate the mechanistic basis of adaptive enhancements of aerobic performance capacity in hypoxia; (2) to determine how regulatory changes in gene expression translate into changes in phenotype at different hierarchical levels of biological organization; and (3) to identify and experimentally test new candidate genes and pathways for hypoxia adaptation. The integration of population genomics, functional genomics, and experimental physiology will advance the field by elucidating the mechanistic basis of adaptive evolutionary change in complex performance traits.

项目摘要高海拔动物已经发展了在氧气剥夺条件下生存和功能的能力（缺氧）模仿人类中的疾病。鉴定缺氧适应的进化机制因此，长期高海拔本地人的哺乳动物可以产生生物医学相关性的发现还提供有关复杂性状演变的一般见解。许多野生啮齿动物物种影响很大比藏族和安第斯人类更极端的高度涉及遗传杂交和侵入性生理操纵的实验方法。这个项目整合基因组学和实验生理学，以剖析自适应增强的机理基础极端高海拔啮齿动物中缺氧的全面性能。实验比较高和低 - 两种物种的高度种群：鹿小鼠（peromyscus maniculatus），它具有最广泛的任何北美哺乳动物的海拔范围（海平面为4350 m），而安第斯叶子的小鼠（Phyllotis vaccarum），一种极端的物种，其记录是世界上最高的哺乳动物和这也具有最广泛的高度范围（海平面至> 6700 m [> 22,000']）。测试有关自适应的假设对缺氧的调节反应，我们将使用共同的实验设计来整合全面的身体表现（缺氧的有氧运动能力）和各种下属特征（呼吸道，心血管和代谢），具有组织特异性的转录组和代谢组谱。实验将涉及高度侵入性的操纵（例如，动脉和静脉的手术仪器在运动试验和重要器官的终末采样期间测量血液气体的导管）在人类受试者中可行。在这两个物种中，机械实验将由人口完成基因组实验以产生有关可能有助于的特定基因和途径的假设适应低氧。然后，将使用后续实验测试此类假设以测量表型基因功能和/或基因表达变化的影响，如我们正在进行的鹿小鼠的工作所示。研究的具体目的是（1）阐明有氧运动的自适应增强的机理基础缺氧的表现能力；（2）确定基因表达的调节变化如何转化为生物组织不同层次级别表型的变化；（3）识别和实验测试新候选基因和缺氧适应性途径。人口的融合基因组学，功能基因组学和实验生理学将通过阐明复杂性能性状的自适应进化变化的机理基础。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

To what extent do physiological tolerances determine elevational range limits of mammals?

DOI：
10.1113/jp284586
发表时间：
2023-10-27
期刊：
JOURNAL OF PHYSIOLOGY-LONDON
影响因子：
5.5
作者：
Storz，Jay F.;Scott，Graham R.
通讯作者：
Scott，Graham R.

Genomic insights into the mystery of mouse mummies on the summits of Atacama volcanoes.

对阿塔卡马火山顶上老鼠木乃伊之谜的基因组见解。

DOI：
10.1016/j.cub.2023.08.081
发表时间：
2023
期刊：
Current biology : CB
影响因子：
0
作者：
Storz,JayF;Liphardt,Schuyler;Quiroga-Carmona,Marcial;Bautista,NaimM;Opazo,JuanC;Wheeler,TimothyB;D'Elía,Guillermo;Good,JeffreyM
通讯作者：
Good,JeffreyM

Elevational range extension of the Puna Mouse, Punomys (Cricetidae), with the first record of the genus from Chile

普纳鼠（Punomys）（仓鼠科）的海拔范围扩展，该属的第一个记录来自智利

DOI：
10.1093/jmammal/gyad064
发表时间：
2023
期刊：
Journal of Mammalogy
影响因子：
1.7
作者：
Quiroga-Carmona, Marcial;Storz, Jay F.;D’Elía, Guillermo;Hawkins, ed., Melissa
通讯作者：
Hawkins, ed., Melissa