Digging up the developmental origins of adaptive physiological plasticity in hypoxia-tolerant mammals

挖掘耐缺氧哺乳动物适应性生理可塑性的发育起源

• 批准号: RGPIN-2020-07119
• 负责人: Pamenter, Matthew
• 金额: $ 3.42万
• 依托单位: University of Ottawa
• 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=745583
• 关键词: Digging; up; developmental; origins; adaptive

Vertebrates rely on continuous oxygen (O2) delivery for aerobic energy production; however, there are terrestrial environments in which O2 availability is limited (e.g., high altitude, underground burrows). Limited O2 availability (i.e., hypoxia) impairs  cellular energy production, and ultimately, survival. Despite these challenges, animals have successfully populated terrestrial hypoxic niches. The key to tolerating hypoxia is matching metabolic demand to reduced energy supply, and vertebrates have evolved a range of adaptive strategies that contribute to this balance. In the most hypoxia-tolerant species, metabolic rate supression is the primary adaptive response to hypoxia. However, despite the importance of energetic homeostasis to survival and the severe limitations that hypoxia imposes on energy production, we do not have a good understanding of the cellular mechanisms that mediate metabolic rate suppression in any hypoxia-tolerant species, or the evolutionary origins of these traits. My goal is to understand how hypoxia-tolerant mammals maintain energetic homeostasis during fluctuations in environmental O2 levels. The research proposed in the present application will build upon recent progress by my laboratory towards this objective by providing new information about 1) physiological adaptations to hypoxia, 2) molecular mechanisms that underlie these adaptations, and 3) the evolution of hypoxia-tolerance at the physiological and molecular levels. We will use the Krogh Principle to address our questions in an evolutionary and developmental context and build upon our recent progress by contrasting physiological and molecular responses to hypoxia between hypoxia-tolerant and -intolerant mammals. Our primary study species include the naked mole-rat, which is arguably the mammalian champion of hypoxia-tolerance and thus an ideal model in which to investigate our research questions, and also moderately hypoxia-tolerant cousin species (Damaraland and Giant Zambian mole-rats), and hypoxia-intolerant mice and rats. We will investigate the following SHORT-TERM OBJECTIVES/QUESTIONS: 1.Which central nervous system signalling mechanisms control physiological adaptations to hypoxia throughout development in African mole-rats? 2.How does mitochondrial plasticity impact systemic energetics in hypoxia-tolerant mammals? 3.What underlies beneficial reactive oxygen species (ROS) management in hypoxia-tolerant mammals? This research will fundamentally advance the field by revealing the evolution of mechanisms that beneficially modulate physiological and cellular energetics to achieve metabolic homeostasis and organismal survival in hypoxia. We will answer important basic research questions regarding the evolution of hypoxia-tolerance in a developmental context. We may also inform translation studies in biomedical fields focused on achieving cytoprotection in hypoxia (e.g., heart attack/stroke).

脊椎动物依靠连续氧（O2）递送来产生有氧能源。但是，有一些陆地环境有限的O2可用性（例如，高海拔，地下洞穴）。有限的O2可用性（即缺氧）会损害细胞能量的产生，并最终损害生存。尽管面临这些挑战，但动物还是成功地填充了陆地低氧壁ni。容忍缺氧的关键是匹配代谢需求以减少能源供应，脊椎动物发展了一系列有助于这种平衡的自适应策略。在最缺氧的物种中，代谢率抑制是对缺氧的主要适应性反应。然而，尽管能量体内稳态对生存的重要性以及缺氧对能量产生的严重局限性，但我们对介导任何耐高氧耐受性物质的代谢率抑制的细胞机制或这些特征的进化起源都没有很好的了解。我的目标是了解环境O2水平波动期间如何维持耐氧哺乳动物的能量稳态。本应用中提出的研究将基于我的实验室最近的进展，通过提供有关1）身体适应性的新信息，2）基于这些适应的分子机制，以及3）3）3）我们将使用Krogh原理在进化和发育中的进步和对偶然性的反应之间的进展来对我们的问题进行质疑 - 与偶然的变化 - 构成了异常的变化 - 哺乳动物。我们的主要研究物种包括赤裸的分子鼠，可以说是哺乳动物耐受耐受性低的哺乳动物拥护者，因此是研究我们的研究问题的理想模型，也是中等耐高氧的表亲（Damaraland和Damaraland和巨大的赞比亚巨鼠），以及低氧智力 - 耐流小鼠和老鼠。我们将研究以下短期目标/问题：1。哪些中枢神经系统信号机制控制着对非洲摩尔大鼠整个发育过程中缺氧的生理适应性？ 2。线粒体可塑性如何影响缺氧哺乳动物的全身能量学？ 3.哪些是耐高氧哺乳动物中有益的活性氧（ROS）管理的基础？这项研究将通过揭示有益的调节生理和细胞能量的机制的演变来从根本上推进该领域，从而实现了代谢稳态和缺氧的有机生存。我们将回答有关在发育环境中低氧耐受性演变的重要基础研究问题。我们还可以为生物医学领域的翻译研究提供信息，该研究集中于实现缺氧的细胞保护作用（例如心脏病/中风）。