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.

Public Health Relevance

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. Populations (e.g., highland Tibetan humans) that have adapted to high-altitude environments are protected from the negative effects of extremely low oxygen availability (hypoxia), in part because they have modified a key hypoxia-signaling pathway known as the hypoxia-inducible factor (HIF) cascade. I propose to use deer mice (Peromyscus maniculatus), which have naturally adapted to high-altitude, as a model to determine the molecular and genetic mechanisms by which heart, lung, and blood responses to hypoxia benefit from Darwinian selection on the HIF cascade. A mechanistic understanding of adaptation to hypoxia will yield insight into novel therapies in the treatment of diseases related to the loss of oxygen homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL136124-01
Application #
9258284
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Meadows, Tawanna
Project Start
2017-04-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Montana
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
010379790
City
Missoula
State
MT
Country
United States
Zip Code
59812
Velotta, Jonathan P; Ivy, Catherine M; Wolf, Cole J et al. (2018) Maladaptive phenotypic plasticity in cardiac muscle growth is suppressed in high-altitude deer mice. Evolution 72:2712-2727