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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087216-02
Application #
7690723
Study Section
Special Emphasis Panel (ZRG1-CVS-A (50))
Program Officer
Luksenburg, Harvey
Project Start
2008-09-22
Project End
2013-06-30
Budget Start
2009-07-29
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$263,352
Indirect Cost
Name
University of Nebraska Lincoln
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588
Storz, Jay F (2018) Compensatory mutations and epistasis for protein function. Curr Opin Struct Biol 50:18-25
Jendroszek, Agnieszka; Malte, Hans; Overgaard, Cathrine B et al. (2018) Allosteric mechanisms underlying the adaptive increase in hemoglobin-oxygen affinity of the bar-headed goose. J Exp Biol 221:
Zhu, Xiaojia; Guan, Yuyan; Signore, Anthony V et al. (2018) Divergent and parallel routes of biochemical adaptation in high-altitude passerine birds from the Qinghai-Tibet Plateau. Proc Natl Acad Sci U S A 115:1865-1870
Hoffmann, Federico G; Vandewege, Michael W; Storz, Jay F et al. (2018) Gene Turnover and Diversification of the ?- and ?-Globin Gene Families in Sauropsid Vertebrates. Genome Biol Evol 10:344-358
Tate, Kevin B; Ivy, Catherine M; Velotta, Jonathan P et al. (2017) Circulatory mechanisms underlying adaptive increases in thermogenic capacity in high-altitude deer mice. J Exp Biol 220:3616-3620
Lau, Daphne S; Connaty, Alex D; Mahalingam, Sajeni et al. (2017) Acclimation to hypoxia increases carbohydrate use during exercise in high-altitude deer mice. Am J Physiol Regul Integr Comp Physiol 312:R400-R411
Kumar, Amit; Natarajan, Chandrasekhar; Moriyama, Hideaki et al. (2017) Stability-Mediated Epistasis Restricts Accessible Mutational Pathways in the Functional Evolution of Avian Hemoglobin. Mol Biol Evol 34:1240-1251
Natarajan, Chandrasekhar; Hoffmann, Federico G; Weber, Roy E et al. (2016) Predictable convergence in hemoglobin function has unpredictable molecular underpinnings. Science 354:336-339
Storz, Jay F (2016) Hemoglobin-oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend? J Exp Biol 219:3190-3203
Storz, Jay F; Cheviron, Zachary A (2016) Functional Genomic Insights into Regulatory Mechanisms of High-Altitude Adaptation. Adv Exp Med Biol 903:113-28

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