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

脊椎动物依赖于持续的氧气（O2）输送来产生有氧能量;然而，存在O2可用性有限的陆地环境（例如，高海拔，地下洞穴）。有限的O2可用性（即，缺氧）损害细胞能量产生并最终损害存活。尽管有这些挑战，动物们还是成功地在陆地缺氧的生态位中定居下来。耐受缺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。在大多数耐缺氧的物种中，代谢率抑制是对缺氧的主要适应性反应。然而，尽管能量稳态对生存的重要性和缺氧对能量产生的严重限制，我们对任何耐缺氧物种中介导代谢率抑制的细胞机制或这些特征的进化起源没有很好的理解。我的目标是了解耐缺氧的哺乳动物如何在环境O2水平波动期间保持能量平衡。本申请中提出的研究将建立在我的实验室朝着这个目标的最新进展的基础上，通过提供关于以下的新信息：1）对缺氧的生理适应，2）这些适应的分子机制，和3）在生理和分子水平上缺氧耐受性的进化。 我们将使用克罗原则来解决我们的问题，在进化和发展的背景下，并建立在我们最近的进展，通过对比生理和分子反应缺氧之间的耐缺氧和不耐缺氧的哺乳动物。我们的主要研究物种包括裸鼹鼠，这可以说是缺氧耐受性的哺乳动物冠军，因此是研究我们研究问题的理想模型，也是中度缺氧耐受的表亲物种（达马拉兰和赞比亚巨型鼹鼠），以及缺氧不耐受的小鼠和大鼠。我们将研究以下短期的实验/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缺氧的生理适应？2.线粒体可塑性如何影响耐缺氧哺乳动物的系统能量学？3.什么是耐缺氧哺乳动物有益的活性氧（ROS）管理的基础？这项研究将从根本上推动该领域的发展，揭示机制的演变，有益地调节生理和细胞能量，以实现代谢稳态和生物体在缺氧中的生存。我们将回答重要的基础研究问题，关于缺氧耐受性的发展背景下的演变。我们还可以告知生物医学领域的翻译研究，重点是实现缺氧中的细胞保护（例如，心脏病发作/中风）。

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).