Mechanisms of Hemoglobin Adaptation to Hypoxia in High-altitude Rodents

高海拔啮齿动物血红蛋白适应缺氧的机制

• 批准号: 8288770
• 负责人: Jay Storz
• 金额: $ 25.78万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288770
• 关键词: Adopted; Adult; Aerobic; Affect; Affinity; Alleles; Altitude; American; Amino Acids; Animals; Binding; Binding Sites; Biochemical; Biochemistry; Biological Assay; Blood; Blood Substitutes; Bohr effect; California; Cell Respiration; Cells; Characteristics; Chloride Ion; Chronic; Complex; Computer Analysis; Computer Simulation; DNA Sequence; Deer Mouse; Disease Management; Embryo; Environment; Equilibrium; Erythrocytes; Exhibits; Genes; Genetic; Genetic Polymorphism; Genotype; Globin; Goals; Health; Hemeproteins; Hemoglobin; Human; Hypoxia; In Vitro; Individual; Interdisciplinary Study; Ligand Binding; Ligands; Mammals; Measurement; Measures; Messenger RNA; Metabolism; Minor; Modeling; Modification; Molecular; Molecular Analysis; Molecular Evolution; Mus; Mutation; Natural Selections; Nevada; Nitric Oxide; North America; Nucleotides; Oxygen; Pattern; Peromyscus; Pharmaceutical Preparations; Phosphoric Acid Esters; Physiological Adaptation; Population; Population Genetics; Process; Property; Protein Biochemistry; Protein Isoforms; Proteins; Protons; Reactive Oxygen Species; Relative (related person); Research; Research Project Grants; Rodent; Role; Sampling; Sea; Stress; Structure; Surveys; System; Temperature; Testing; Therapeutic; Tissues; Transcript; Transcriptional Regulation; Variant; base; candidate identification; design; diphosphoglycerate; duplicate genes; experimental analysis; gene therapy; genetic analysis; human disease; insight; molecular site; novel; oxygen transport; protein structure function; research study; stoichiometry; structural biology; theories; tool

DESCRIPTION (provided by applicant): The purpose of the proposed research project is to elucidate the molecular basis of physiological adaptation to high-altitude hypoxia, a condition resulting from a reduced supply of oxygen to the cells of respiring tissues. Specifically, the proposed research will involve a structural and functional analysis of hemoglobin variation that is associated with adaptive variation in the blood biochemistry and aerobic metabolism of high-altitude deer mice (Peromyscus maniculatus). Insights into the molecular mechanisms that allow high-altitude animals to survive and function under conditions of chronic hypoxia can aid our understanding and management of disease processes in humans that compromise the oxygen transport system. By identifying the molecular underpinnings of hypoxia tolerance, it may be possible to replicate the mechanism with novel drug-based therapy, gene therapy, and hemoglobin-based blood substitutes. This highly interdisciplinary study will integrate the tools and theory of molecular population genetics, molecular evolution, structural biology, and protein biochemistry. The specific aims of this research project are (1) To identify the specific amino acid mutations that are responsible for hemoglobin adaptation to hypoxia; (2) To assess whether modifications of hemoglobin structure are also associated with regulatory adjustments in the composition stoichiometry of different hemoglobin isoforms in circulating red blood cells; and (3) To assess the functional consequences of the observed structural and regulatory changes. After first conducting a population-level survey of DNA sequence variation to identify naturally occurring mutations in the globin genes of high-altitude deer mice, this study will involve a population-genetic analysis to infer which of the observed amino-acid changes may be attributable to positive Darwinian selection, an analysis of regulatory variation at the mRNA and protein levels, an 'in silico' computational analysis to predict effects on hemoglobin-oxygen affinity, and an 'in vitro' experimental analysis to assess how the identified structural and regulatory changes influence intrinsic oxygen affinity, as well as sensitivities to temperature, protons (Bohr effect), allosteric effectors, and metabolism of reactive oxygen species and nitric oxide. By identifying mechanisms of hemoglobin adaptation that have evolved in natural populations of high-altitude rodents, the proposed research project should provide novel insights into the molecular basis of hypoxia tolerance. PUBLIC HEALTH RELEVANCE: The goal of the proposed research project is to identify the specific changes in hemoglobin function that have evolved in mice that are native to high-altitude environments. By identifying the specific molecular mechanisms that have enabled high-altitude animals to survive and function under low oxygen conditions, it may be possible to replicate the mechanism in therapeutic treatments of human diseases that compromise the oxygen transport system.

描述（由申请人提供）：拟议的研究项目的目的是阐明生理适应高海拔低氧的分子基础，这是由于减少氧气供应减少对呼吸组织细胞的供应所致。具体而言，拟议的研究将涉及血红蛋白变异的结构和功能分析，这与血液化学的适应性变异和高空鹿小鼠的有氧代谢有关（peromyscus maniculatus）。洞悉允许高空动物在慢性缺氧条件下生存和功能的分子机制可以帮助我们理解和管理损害氧气传输系统的人类疾病过程。通过鉴定缺氧耐受性的分子基础，可以通过新型的基于药物的治疗，基因疗法和基于血红蛋白的血液替代品复制该机制。这项高度的跨学科研究将整合分子种群遗传学，分子进化，结构生物学和蛋白质生物化学的工具和理论。该研究项目的具体目的是（1）确定负责血红蛋白适应低氧的特定氨基酸突变； （2）评估血红蛋白结构的修饰是否也与循环红细胞中不同血红蛋白同工型组成化学计量的调节调节相关； （3）评估观察到的结构和调节变化的功能后果。 After first conducting a population-level survey of DNA sequence variation to identify naturally occurring mutations in the globin genes of high-altitude deer mice, this study will involve a population-genetic analysis to infer which of the observed amino-acid changes may be attributable to positive Darwinian selection, an analysis of regulatory variation at the mRNA and protein levels, an 'in silico' computational analysis to predict effects on血红蛋白 - 氧亲和力以及“体外”实验分析，以评估确定的结构和调节性变化如何影响内在的氧亲和力，以及对温度，质子（BOHR效应），变构效应子，反应性氧和氧化氧化物的代谢的敏感性。通过鉴定在高海拔啮齿动物自然种群中进化的血红蛋白适应的机制，提出的研究项目应提供对缺氧耐受性分子基础的新见解。公共卫生相关性：拟议的研究项目的目标是确定在高海拔环境的小鼠中进化的血红蛋白功能的特定变化。通过确定使高空动物在低氧气条件下生存和功能的特定分子机制，可以复制损害氧气传输系统的人类疾病治疗治疗中的机制。