Mechanisms and Evolution of Hypoxia Tolerance

耐缺氧的机制和进化

• 批准号: RGPIN-2020-04527
• 负责人: Richards, Jeffrey
• 金额: $ 4.74万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740018
• 关键词: Mechanisms; Evolution; Hypoxia; Tolerance

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.

对于大多数空气呼吸脊椎动物，环境氧（称为缺氧）的减少是罕见的。当它们确实发生时，它们可能会带来毁灭性的代谢后果，导致死亡。但是，在水生环境中，氧气水平可能大大差异，从比正常高的水平到完全没有氧气的水平。结果，居住在这些不同环境（尤其是鱼）中的水呼吸脊椎动物表现出高度差异的较高的耐水性差异，这并不奇怪。尽管进行了数十年的研究，但我们仍然没有完全了解鱼类中缺氧耐受性的差异以及解释为什么某些鱼比其他人更容易受到低氧暴露的负面后果的机制的差异。为了解决这一知识差距，我的研究计划使用了密切相关的鱼类种群中观察到的缺氧耐受性的自然变化，以了解低氧耐受性的机制和演变。我们的主要比较模型涉及多种称为sculpins的鱼类，我们是从海岸环境附近的海洋中收集的，并显示出低氧耐受性的差异。基于我们在雕塑和其他比较模型中的工作，我们确定了三个主要因素，这些因素有助于解释缺氧耐受性的差异。首先，我们已经确定了线粒体，通常称为“细胞的强大体积”，是对缺氧的适应性的联系。其次，我们发现了一个独特的基因表达特征，可以区分低氧耐受性和不宽容的丝素。最后，我们证明缺氧耐受性与“关闭”代谢和抑制新陈代谢率的能力有关。该NSERC-DG提案建立在这些主要发现基础上，并旨在阐明定义低氧耐受性的详细生理，生化和分子机制。对这种性质的研究很重要，因为它有助于预测哪些生物体由于人类引起的气候变化以及水生缺氧的相关增加而面临的风险最高。此外，我们的详细机械工作是发现氧生物学的基本方面的独特定位，这些方面可以帮助发现人类中氧相关条件的重要途径，包括癌症和心脏病发作。这笔赠款将使我能够以最先进的分析和概念方法来培训5名毕业生（3博士学位和2个MSC）和2名本科生（1个BSC荣誉和1名NSERC-ISRA）学生，以了解动物如何与环境互动。