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

• 批准号: 10446130
• 负责人: Jay Storz
• 金额: $ 52.58万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 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/10446130
• 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; Evolution; Exercise; Experimental Designs; Feedback; Gardenal; Gene Expression; Genes; Genetic; Genetic Crosses; Genetic Polymorphism; Genetic Transcription; Genome Scan; Genomics; Genotype; Goals; Human; Hypoxia; Hypoxia Pathway; Lead; 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; Play; Population; Research; Research Project Grants; Resistance; Rodent; Role; 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; mouse genome; novel; novel therapeutic intervention; programs; respiratory; response; stem; trait; transcription factor; transcriptomics

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.

项目总结 高海拔动物进化出了在缺氧条件下生存和活动的能力 (缺氧)模仿人类疾病状态的疾病。确定低氧适应的进化机制 因此，长期生活在高海拔地区的哺乳动物可以产生与生物医学相关的发现，而 还提供了对复杂特征进化的一般见解。许多野生啮齿动物物种栖息在遥远的 比藏族和安第斯人更极端的海拔，也代表着更容易驯服的主题 涉及基因杂交和侵入性生理操作的实验方法。这个项目 结合基因组学和实验生理学，剖析适应性增强的机制基础 极端高海拔啮齿动物在低氧条件下的整体表现。这些实验比较了高-和低- 两个物种的海拔种群：鹿鼠(Permyscus Manulatus)，它拥有最广泛的 任何北美哺乳动物的海拔范围(海平面到4350米)，以及安第斯叶耳鼠 (Phyllotis Vvarum)，一种极端生物物种，保持着世界最高栖息地哺乳动物的记录，并 这也是海拔范围最广的(海平面到6700米[&gt；22,000‘])。检验关于适应性的假设 对于低氧的调节反应，我们将使用共同花园实验设计来整合 全动物生理表现(低氧下的有氧运动能力)及各种从属性状 (呼吸、心血管和代谢)，具有组织特定的转录和代谢组学特征。 实验将涉及高侵入性操作(例如，动脉和静脉的外科器械 在运动试验和重要器官的终端采样期间测量血气的导管) 在人体实验中是可行的。在这两个物种中，机械实验将得到种群的补充。 基因组实验，以产生关于可能起作用的特定基因和途径的假说 低氧适应。然后将使用后续实验来测试这些假设，以测量表型 基因功能和/或基因表达变化的影响，正如我们正在进行的鹿鼠研究所表明的那样。 本研究的具体目的是：(1)阐明有氧运动适应性增强的机制基础 耐低氧能力；(2)确定基因表达的调节变化如何转化为 生物组织不同层级的表型变化；以及(3)识别和 实验测试新的低氧适应候选基因和途径。人口一体化 基因组学、功能基因组学和实验生理学将通过阐明 复杂表现性状适应性进化变化的机制基础。