The evolution of ketone body metabolism and hypoxia tolerance

酮体代谢和缺氧耐受性的演变

• 批准号: RGPIN-2020-07099
• 负责人: Morash, Andrea
• 金额: $ 2.04万
• 依托单位: Mount Allison University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745822
• 关键词: evolution; ketone; body; metabolism; hypoxia

The long-term goal of my research is to understand how vertebrates respond to environmental stress through changes in substrate use and mitochondrial function. In particular, I am interested in understanding the evolution of the hypoxic response and the capacity for mitochondrial ketone body metabolism to protect against hypoxic damage. My goals for this proposal are to use a comparative approach to test the following hypotheses: Theme 1) Ketone body metabolism protects high energy tissues (brain, heart) from the oxidative stress associated with lipid metabolism. (HQP: 1 MSc and 5 BSc students over 5 years). Experiments in this theme will compare highly active (heart, brain) vs. less active (resting muscle) tissues from elasmobranchs, sturgeon and teleost fish to understand how different tissues using ketone bodies to generate ATP can protect against oxidative stress versus those using lipids. Theme 2) Chronic hypoxia will cause a whole animal ketogenic response (HQP: 1 MSc and 5 BSc over 5 years). Experiments in this theme will determine metabolic fuel use during chronic hypoxia in elasmobranchs, sturgeon and teleost fish, and test whether there is a ketogenic response in these animal groups. The metabolic profiles will be correlated to whole animal measures of hypoxia tolerance. Theme 3) Ketone body metabolism is both part of, and regulates, the hypoxic response (HQP: 5 BSc. over 5 years). We currently have little information on potential pathways for regulating ketone body metabolism in fish, or on their potential role in the hypoxic response. Experiments in this theme will seek to identify the regulatory mechanisms controlling ketogenesis, and the role of ketone bodies in facilitating the hypoxic response in various tissues. Training Impact: HQP will gain highly sought transferable skills applicable to a broad range of evidence-based careers. Students will be equipped with skills in project management, critical thinking and problem solving, data management and analysis, and effective presentation skills. Through engagement with my collaborators, HQP will understand the benefits of interdisciplinary collaboration and gain the skills to foster working relationships. Scientific Impact: Hypoxic dead zones and oxygen minima zones are increasing in extent and duration globally. Coastal systems are impacted heavily by nutrification that drives down dissolved oxygen, while increasing temperature further exacerbates this issue. Research on mitochondrial physiology of aquatic organisms will help to understand the evolution of energy production in aquatic species, and will also help us to predict how these species may respond to climate change and the predicted increase in aquatic hypoxia. Species specific information will help inform ecological changes within ecosystems and understand why some organisms are outperforming others.

我研究的长期目标是了解脊椎动物如何通过底物使用和线粒体功能的变化来应对环境压力。特别是，我有兴趣了解缺氧反应的演变和线粒体酮体代谢的能力，以防止缺氧损伤。我的这个建议的目标是使用比较的方法来测试以下假设：主题1）酮体代谢保护高能量组织（大脑，心脏）从与脂质代谢相关的氧化应激。(HQP：1名理学硕士和5名理学学士学生超过5年）。这个主题的实验将比较来自板鳃类、鲟鱼和硬骨鱼的高活性（心脏、大脑）与低活性（静息肌肉）组织，以了解使用酮体产生ATP的不同组织如何与使用脂质的组织对抗氧化应激。 主题2）慢性缺氧将导致整个动物的生酮反应（HQP：5年内1个MSc和5个BSC）。这一主题的实验将确定在慢性缺氧期间板鳃类，鲟鱼和硬骨鱼的代谢燃料使用，并测试这些动物群体中是否有生酮反应。代谢谱将与整个动物的缺氧耐受性测量相关。主题3）酮体代谢既是缺氧反应的一部分，又调节缺氧反应（HQP：5理学士。5年以上）。我们目前几乎没有信息的潜在途径，调节酮体代谢的鱼类，或在缺氧反应中的潜在作用。在这个主题的实验将寻求确定控制生酮的调节机制，以及酮体在促进各种组织的缺氧反应中的作用。培训影响：HQP将获得适用于广泛的循证职业的备受追捧的可转移技能。学生将具备项目管理，批判性思维和解决问题，数据管理和分析，以及有效的演讲技巧的技能。通过与我的合作者的接触，HQP将了解跨学科合作的好处，并获得培养工作关系的技能。科学影响：缺氧死区和氧气最低区在全球范围内的范围和持续时间都在增加。沿海系统受到营养化的严重影响，导致溶解氧下降，而温度升高进一步加剧了这一问题。对水生生物线粒体生理学的研究将有助于了解水生物种能量生产的演变，也将有助于我们预测这些物种可能如何应对气候变化和预测的水生缺氧增加。特定物种的信息将有助于告知生态系统内的生态变化，并了解为什么一些生物体优于其他生物体。