Mechanisms and Evolution of Hypoxia Tolerance

对于大多数呼吸空气的脊椎动物来说，环境氧气的减少（称为缺氧）是罕见的;当它们发生时，它们可能会产生毁灭性的代谢后果，导致死亡。然而，在水生环境中，氧气水平可以有很大的变化，从比正常高出许多倍的水平到完全没有氧气。因此，栖息在这些不同环境中的水呼吸脊椎动物，特别是鱼类，在缺氧耐受性方面表现出高度的差异，这并不奇怪。尽管经过几十年的研究，我们仍然没有完全了解解释为什么鱼类缺氧耐受性存在差异的因素，以及解释为什么某些鱼类比其他鱼类更容易受到缺氧暴露的负面影响的机制。为了解决这一知识差距，我的研究计划使用密切相关的鱼类群体之间观察到的缺氧耐受性的自然变化来了解缺氧耐受性的机制和进化。我们的主要比较模型涉及多个物种的鱼称为sculpins，我们收集从海洋附近的海岸环境，并表现出很大的差异缺氧耐受性。根据我们在杜父鱼和其他比较模型中的工作，我们已经确定了三个主要因素，有助于解释缺氧耐受性的变化。首先，我们已经确定了神经元，这是通常被称为“发电站的细胞”，作为一个适应缺氧的关系。其次，我们发现了一个独特的基因表达特征，区分耐缺氧和不耐杜父鱼。最后，我们证明了缺氧耐受性与“关闭”代谢和抑制代谢率的能力有关。这个NSERC-DG建议建立在这些主要发现的基础上，旨在阐明定义缺氧耐受性的详细生理，生化和分子机制。这种性质的研究很重要，因为它有助于预测哪些生物由于人类引起的气候变化和相关的水生缺氧增加而面临最大的风险。此外，我们详细的机械工作具有独特的优势，可以发现氧生物学的基本方面，这可以帮助揭示人类与氧相关疾病的重要途径，包括癌症和心脏病发作。这笔赠款将允许我每年培训5名研究生（3名博士和2名硕士）和2名本科生（1名荣誉理学士和1名NSERC-USRA），以了解动物如何与环境相互作用的最先进的分析和概念方法。

For most air-breathing vertebrates, decreases in environmental oxygen (referred to as hypoxia) are a rare occurrence; when they do occur, they can have devastating metabolic consequences resulting in death. In aquatic environments however, oxygen levels can vary substantially, from levels that are many-fold higher than normal to the complete absence of oxygen. As a result, it is not surprising that the water-breathing vertebrates that inhabit these diverse environments, particularly fish, show a high level of variation in hypoxia tolerance. Despite several decades of study, we still do not have a complete understanding of the factors that explain why there is variation in hypoxia tolerance among fish and the mechanisms that explain why some fish are more susceptible to the negative consequences of hypoxia exposure than others. To address this knowledge gap, my research program uses the natural variation in hypoxia tolerance observed among groups of closely related fish species to understand the mechanisms and evolution of hypoxia tolerance. Our primary comparative model involves multiple species of fish called sculpins, which we collect from the marine near shore environment and show a large variation in hypoxia tolerance. Based upon our work in sculpins and other comparative models, we have identified three major factors that contribute to explaining variation in hypoxia tolerance. First, we have identified the mitochondrion, which is often referred to as "the powerhouse of the cell", as a nexus of adaptation to hypoxia. Second, we have uncovered a unique gene expression signature that differentiates hypoxia tolerant and intolerant sculpins. Finally, we demonstrate that hypoxia tolerance is associated with the ability to "turn off" metabolism and suppress metabolic rate. This NSERC-DG proposal builds upon these major findings and aims to elucidate the detailed physiological, biochemical, and molecular mechanisms that define hypoxia tolerance. Research of this nature is important as it assists in predicting which organisms are most at risk due to human-induced climate change and the associated increases in aquatic hypoxia. In addition, our detailed mechanistic work is uniquely positioned to discover fundamental aspects of oxygen biology, which could assist in uncovering important pathways underlying oxygen related conditions in humans, including cancer and heart attack. This grant will allow me to train 5 graduate (3 PhD & 2 MSc) and 2 undergraduate (1 BSc Honors & 1 NSERC-USRA) students per year in the most advanced analytical and conceptual approaches for understanding how animals interact with their environment.