Evolved mechanisms of hypoxia resistance in high-altitude natives

通过氧气传输级联反应(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)将氧气适当地分配到线粒体，这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运输级联进化的潜在机制，并了解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O2级联的进化如何有助于高海拔低氧环境中天然动物的耐低氧(低O2)。我们已经建立了来自高海拔和低海拔的鹿鼠实验室繁殖群体，作为一个强大的研究系统，使我们能够理清进化(基于基因)和环境诱导(塑料)在生理和性能上的变化。我们已经证明，高海拔小鼠在低氧条件下进化出了增强的氧气运输能力(VO2max)，同时骨骼肌的生理和分子变化增加了组织的氧气扩散和线粒体的氧气利用。然而，关于肺和心血管系统在VO2max进行性增加中的作用，人们知之甚少。目前也不清楚高海拔小鼠如何避免慢性低氧暴露的适应不良影响，这是许多高海拔疾病的特征。这项拟议的研究将着眼于三个短期目标：(1)表征有助于高原鹿小鼠适应增加VO2max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影响；以及(3)阐明耐缺氧进化和O2传输级联的遗传基础。我们将利用比较方法和心肺技术，这些技术在我的实验室已经很好地建立起来了。我们还将利用一个独特的合作机会来发现两个有希望的高原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使我能够培训至少4名博士、4名理学硕士和20名理科学生，他们将获得对许多科学职业都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洞察，通过阐明自然进化的氧气匮乏解决方案(这是与人类和动物的许多临床疾病相关的问题)，并揭示进化和可塑性如何促进或限制海拔范围的变化，以应对气候变化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.