The evolution of ketone body metabolism and hypoxia tolerance

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，我对了解低氧反应的演变和线粒体酮体代谢保护低氧损伤的能力感兴趣。我对这项提议的目标是用比较的方法来检验以下假设： 主题1)酮体代谢保护高能组织(脑、心脏)免受与脂类代谢相关的氧化应激。(HQP：5年以上1名硕士和5名理科学生)。这一主题的实验将比较来自棘鳃、鲟鱼和硬骨鱼的高活性(心脏、大脑)和不太活跃的(休眠肌肉)组织，以了解使用酮体产生ATP的不同组织与使用脂质的组织如何防止氧化应激。 主题2)慢性低氧将导致整个动物的生酮反应(HQP：5年内1个硕士和5个BSC)。这一主题的实验将确定棘鳃、鲟鱼和硬骨鱼在慢性缺氧期间代谢燃料的使用，并测试这些动物组是否有生酮反应。代谢谱将与整个动物耐缺氧的措施相关联。 主题3)酮体代谢既是缺氧反应的一部分，也是调节缺氧反应的一部分(HQP：5 BSC。超过5年)。目前，我们对鱼类体内酮体代谢调节的潜在途径，或它们在低氧反应中的潜在作用，知之甚少。这一主题的实验将试图确定控制酮的发生的调节机制，以及酮小体在促进各种组织的缺氧反应中的作用。 培训影响：HQP将获得广受欢迎的可转移技能，适用于广泛的循证职业。学生将掌握项目管理、批判性思维和解决问题、数据管理和分析的技能，以及有效的演示技能。通过与我的合作者接触，HQP将了解跨学科协作的好处，并获得培养工作关系的技能。 科学影响：全球范围内缺氧死亡区和低氧区的范围和持续时间都在增加。沿海系统受到营养作用的严重影响，营养作用降低了溶解氧，而气温上升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生物能量生产的进化，也将有助于我们预测这些物种如何应对气候变化和预计的水生缺氧加剧。物种特有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的表现优于其他生物。

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.