Evolved mechanisms of hypoxia resistance in high-altitude natives

通过氧气转运级联（呼吸、氧气在呼吸表面的扩散、氧气在血液中的循环、组织氧气扩散和线粒体氧气利用）将氧气充分分配到线粒体对健康和健身至关重要，但我们对这一综合生理系统的进化知之甚少。我的研究计划的长期目标是了解O2运输级联进化的机制，并欣赏这些机制在脊椎动物中的多样性。我最近的研究重点是了解氧气级联的进化如何促进高海拔低氧环境下动物的缺氧（低氧）抵抗。我们已经在高海拔和低海拔地区建立了鹿鼠的实验室繁殖群，作为一个强大的研究系统，使我们能够摆脱生理和性能上的进化（遗传基础）和环境诱导（塑料）变化。我们已经证明，高海拔小鼠已经进化出了在缺氧条件下增强的氧气运输能力（VO2max），同时骨骼肌的生理和分子变化也增强了组织氧气的扩散和线粒体氧气的利用。然而，关于肺和心血管系统在VO2max进化增加中的作用知之甚少。目前还不清楚，高原小鼠如何避免慢性缺氧暴露的不良影响，这是许多高原疾病的特征。本研究将解决三个短期目标：(1)确定高原鹿小鼠缺氧条件下VO2max适应性增加的肺和心血管机制；(2)解释高原小鼠如何克服慢性缺氧的适应不良效应；(3)阐明耐缺氧进化和氧转运级联的遗传基础。我们将利用比较方法和心肺技术，这在我的实验室里已经很成熟了。我们还将利用一个独特的合作机会来揭示两个有希望的高海拔适应候选者的生理重要性：血红蛋白和缺氧诱导因子（HIF） 2。在这个资助周期中申请的资金将允许我培养至少4名博士，4名硕士和20名理学士学生，他们将获得对许多科学事业非常宝贵的高级技能。这项工作预计将产生广泛的影响，通过提供对进化适应的综合生理机制的基本见解，通过阐明氧气剥夺的自然进化解决方案（一个与人类和动物的许多临床疾病相关的问题），并通过揭示进化和可塑性如何促进或限制海拔范围的变化以响应气候变化，这是加拿大和世界各地日益严重的环境问题。

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.