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

脊椎动物依靠持续的氧气(O2)输送来产生有氧能量；然而，在陆地环境中，O2的可用性是有限的(例如，高海拔、地下洞穴)。有限的氧气供应(即低氧)会损害细胞的能量生产，并最终损害细胞的存活。尽管有这些挑战，动物已经成功地在陆地上生长了低氧的生态位。耐受低氧的关键是使代谢需求与减少的能量供应相匹配，脊椎动物已经进化出一系列有助于这种平衡的适应策略。在最耐缺氧的物种中，代谢率抑制是对缺氧的主要适应性反应。然而，尽管能量平衡对生存的重要性和低氧对能量产生的严重限制，我们对任何耐低氧物种中调节代谢率抑制的细胞机制，或者这些特征的进化起源，都没有很好的理解。 我的目标是了解耐缺氧的哺乳动物如何在环境氧气水平的波动中保持能量平衡。本申请中提出的研究将建立在我的实验室朝着这一目标的最新进展的基础上，通过提供关于1)对低氧的生理适应，2)这些适应的分子机制，以及3)生理和分子水平的耐低氧进化的新信息。 我们将使用Krogh原理在进化和发育的背景下解决我们的问题，并通过对比耐缺氧和不耐缺氧的哺乳动物对缺氧的生理和分子反应来建立我们最近的进展。我们的主要研究物种包括裸鼠，它可以说是哺乳动物耐缺氧的冠军，因此是研究我们研究问题的理想模型，还有中等耐缺氧的近亲物种(Damaraland和巨型赞比亚鼹鼠)，以及耐缺氧的小鼠和大鼠。 我们将调查以下短期目标/问题： 1.在非洲鼹鼠的整个发育过程中，哪些中枢神经系统信号机制控制着对低氧的生理适应？ 2.线粒体的可塑性如何影响耐缺氧哺乳动物的系统能量学？ 3.耐低氧哺乳动物体内有益的活性氧(ROS)管理的基础是什么？ 这项研究将通过揭示有益地调节生理和细胞能量学以实现代谢动态平衡和有机体在低氧中生存的机制的演变，从根本上推进该领域的发展。我们将回答有关发育背景下耐缺氧进化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参考，这些研究侧重于在低氧(例如，心脏病发作/中风)中实现细胞保护。

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).