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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717086
• 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.

对于大多数呼吸空气的脊椎动物来说，环境氧气减少(称为缺氧)是罕见的；一旦发生，它们可能会产生毁灭性的新陈代谢后果，导致死亡。然而，在水生环境中，氧气水平可能会有很大的差异，从比正常水平高出许多倍到完全没有氧气。因此，生活在这些不同环境中的水生脊椎动物，特别是鱼类，表现出高度的耐缺氧能力也就不足为奇了。尽管经过了几十年的研究，但我们仍然没有完全了解为什么鱼类对缺氧的耐受性存在差异的因素，以及为什么一些鱼类比其他鱼类更容易受到低氧暴露的负面影响的机制。为了解决这一知识差距，我的研究计划使用在密切相关的鱼类种群之间观察到的耐低氧能力的自然变化来了解耐低氧能力的机制和进化。我们的主要比较模型涉及多个种类的鱼，我们从海洋近岸环境中收集的鱼，显示出耐缺氧能力的巨大差异。基于我们在Sculins和其他比较模型中的工作，我们确定了有助于解释低氧耐受性变化的三个主要因素。首先，我们已经确定线粒体是适应低氧的纽带，常被称为“细胞的动力库”。其次，我们发现了一种独特的基因表达特征，它区分了耐缺氧和不耐受雕塑。最后，我们证明了耐缺氧与“关闭”新陈代谢和抑制代谢率的能力有关。NSERC-DG的这项建议建立在这些主要发现的基础上，旨在阐明定义低氧耐受的详细生理、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在发现氧生物学的基本方面方面具有独特的地位，这可能有助于揭示人类氧相关疾病的重要途径，包括癌症和心脏病发作。这笔助学金将允许我每年培训5名研究生(3名博士和2名硕士)和2名本科生(1名理学学士和1名NSERC-USRA)，学习最先进的分析和概念方法，了解动物如何与环境相互作用。