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/文摘