Evolved mechanisms of hypoxia resistance in high-altitude natives

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The adequate partitioning of O2 to mitochondria via the O2 transport cascade (breathing, O2 diffusion across the respiratory surface, circulation of O2 in blood, tissue O2 diffusion, and mitochondrial O2 utilization) is critical to health and fitness, but we know relatively little about the evolution of this integrated physiological system. The long-term objective of my research program is to understand the mechanisms underlying the evolution of the O2 transport cascade, and to appreciate the diversity of these mechanisms across vertebrates. My recent research focuses on understanding how the evolution of the O2 cascade contributes to hypoxia (low O2) resistance in animals native to the hypoxic environment at high altitude. We have established lab breeding colonies of deer mice from high and low altitudes as a powerful study system that allows us to disentangle evolved (genetically based) and environmentally-induced (plastic) changes in physiology and performance. We have shown that high-altitude mice have evolved an enhanced capacity for O2 transport in hypoxia (VO2max), along with physiological and molecular changes in the skeletal muscle that augment tissue O2 diffusion and mitochondrial O2 utilization. However, little is known about the role of pulmonary and cardiovascular systems in the evolved increases in VO2max. It is also unclear how high-altitude mice avoid the maladaptive effects of chronic hypoxia exposure that characterize many high-altitude diseases. The proposed research will address three short-term objectives: (1) characterize the pulmonary and cardiovascular mechanisms that contribute to adaptive increases in VO2max in hypoxia in high-altitude deer mice; (2) explain how high-altitude mice overcome maladaptive effects of chronic hypoxia; and (3) elucidate the genetic basis for the evolution of hypoxia resistance and the O2 transport cascade. We will make use of comparative approaches and cardiorespiratory techniques that are well established in my lab. We will also capitalize on a unique collaborative opportunity to uncover the physiological importance of two promising candidates for high-altitude adaptation: haemoglobin and hypoxia inducible factor (HIF) 2. The funding requested in this grant cycle will allow me to train at least 4 PhD, 4 MSc, and 20 BSc students, who will obtain advanced skills that are invaluable for many scientific careers. The work is expected to have a broad impact, by offering fundamental insight into the integrative physiological mechanisms of evolutionary adaptation, by elucidating naturally evolved solutions to O2 deprivation (a problem associated many clinical disorders in humans and animals), and by revealing how evolution and plasticity might facilitate or constrain altitudinal range shifts in response to climate change a growing environmental problem in Canada and around the world.