Natural selection on the hypoxia-inducible factor pathway and its effects on cardiorespiratory adaptations to low oxygen availability at high-altitude

缺氧诱导因子途径的自然选择及其对高海拔低氧利用率心肺适应的影响

• 批准号: 9258284
• 负责人: Jonathan Paul Velotta
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258284
• 关键词: Aerobic; Affect; Alleles; Altitude; Altitude Sickness; Attenuated; Biological Assay; Biological Models; Blood; Blood Vessels; Blood capillaries; Bone Marrow; Breeding; Cerebrovascular Disorders; Chronic; Chronic lung disease; Deer Mouse; Disease; Dissection; Environment; Erythrocytes; Erythropoiesis; Fiber; Functional disorder; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Models; Genetic Variation; Genomics; Genotype; Goals; Growth; Heart; Heart Diseases; Heart Hypertrophy; Homeostasis; Human; Human Characteristics; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Incidence; Link; Lung; Maintenance; Measures; Mediating; Metabolic; Modeling; Molecular; Molecular Genetics; Mus; Muscle; Mutation; Natural Selections; Organism; Oxygen; Pattern; Performance; Peromyscus; Phenotype; Physiological; Physiological Adaptation; Physiology; Population; Population Characteristics; Pregnancy Outcome; Production; Recording of previous events; Regulation; Research; Respiratory physiology; Series; Signal Pathway; Signal Transduction; Skeletal Muscle; Testing; Therapeutic; Tissues; Variant; Work; angiogenesis; capillary; constriction; density; experience; experimental study; fitness; genome wide association study; insight; novel; novel therapeutics; protein expression; reproductive success; response; transcriptome sequencing; vasoconstriction

Project Summary/Abstract The disruption of oxygen homeostasis is a crucial feature in the pathophysiology of many common and devastating diseases, including heart disease, chronic lung disease, and cerebrovascular disease. Highland natives of the Tibetan plateau, whose ancestors arrived ~25,000 years ago, are protected from high incidence of disease related to low oxygen availability (hypoxia) in part because they have evolved a reduced responsiveness to its harmful effects. The genetic basis of hypoxia adaptation in Tibetans is related to natural selection at the gene epas1, a master regulator of the hypoxia-inducible factor (HIF) pathway that controls physiological responses to hypoxia. Dissection of the mechanisms by which selection at epas1 results in beneficial responses to hypoxia is hampered by the lack of a tractable model, but will ultimately provide key insights into novel therapies related to the loss of oxygen homeostasis. In this series of studies, I will use the deer mouse (Peromyscus maniculatus) to test the hypothesis that genetic variation at epas1 facilitates adaptive cardiorespiratory responses to hypoxia, and to detail the molecular mechanisms that underlie such adaptations. Deer mice live at both high- and low-altitudes, and like highland Tibetans, natural patterns of allele frequency variation suggest that epas1 has been a target of selection in high-altitude populations. I will link epas1 genetic variation to adaptive cardiorespiratory changes by breeding mice of known epas1 genotype under hypoxia and testing for effects on heart, lung, and blood function and Darwinian fitness (Aim 1). I will then use RNA-seq and protein expression assays to characterize the molecular mechanisms underlying physiological effects of epas1 variation at high-altitude by associating genotypic differences in HIF-cascade regulation with differences in cardiorespiratory function (Aim 2). Finally, I will verify that experimental results are applicable in a natural context by associating genetic variation at epas1 with cardiorespiratory physiology and gene expression in a wild, admixed population of high-altitude mice (Aim 3). This work will advance our understanding of the mechanisms of adaptation to high-altitude, which may in turn provide novel insights into therapeutic strategies for hypoxia-related disease.

项目总结/摘要 氧稳态的破坏是许多常见的和不常见的肿瘤的病理生理学中的重要特征。 严重的疾病，包括心脏病、慢性肺病和脑血管疾病。高地 西藏高原的原住民，他们的祖先在25,000年前到达这里， 与低氧可用性（缺氧）相关的疾病的部分原因是它们已经进化出减少的 对其有害影响的反应。藏族低氧适应的遗传基础与自然环境有关， 选择基因epas 1，这是低氧诱导因子（HIF）途径的主要调节因子， 对缺氧的生理反应在epas 1的选择导致的机制剖析， 由于缺乏易处理的模型，对缺氧的有益反应受到阻碍，但最终将提供关键的 与氧稳态丧失相关的新疗法的见解。在这一系列的研究中，我将使用 鹿鼠（Peromyscus maniculatus），以检验epas 1的遗传变异有助于 适应性心肺反应缺氧，并详细的分子机制， 适应鹿鼠生活在高海拔和低海拔地区，和高原藏族一样， 频率变异表明epas 1是高海拔种群选择的目标。我将链接 通过繁殖已知epas 1基因型的小鼠获得epas 1遗传变异以适应心肺变化 在缺氧条件下，测试对心脏、肺和血液功能以及达尔文适应性的影响（目标1）。我会 然后使用RNA-seq和蛋白质表达分析来表征潜在的分子机制， 高海拔地区epas 1变异的生理效应与HIF级联反应中的基因型差异相关 调节与心肺功能的差异（目的2）。最后，我将验证实验结果， 通过将EPAS 1的遗传变异与心肺生理学相关联 和基因表达在一个野生的，混合人口的高海拔小鼠（目的3）。这项工作将促进我们的 了解适应高海拔的机制，这反过来可能提供新的见解， 缺氧相关疾病的治疗策略。