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

脊椎动物依靠连续的氧气输送来产生有氧能量；然而，在陆地环境中，氧气的可用性是有限的（例如，高海拔、地下洞穴）。有限的氧气可用性（即缺氧）损害细胞能量的产生，并最终影响生存。尽管存在这些挑战，动物们还是成功地在陆地缺氧生态位中生存了下来。耐受缺氧的关键是将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适应策略来维持这种平衡。在大多数耐缺氧物种中，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，我们还没有很好地理解在任何耐缺氧物种中介导代谢率抑制的细胞机制，或者这些特征的进化起源。我的目标是了解耐缺氧哺乳动物如何在环境氧气水平波动时保持能量稳态。本申请中提出的研究将以我的实验室最近的进展为基础，通过提供以下方面的新信息：1)对缺氧的生理适应，2)这些适应的分子机制，以及3)生理和分子水平上缺氧耐受性的进化。我们将使用克拉夫原理在进化和发育背景下解决我们的问题，并通过对比耐缺氧和不耐缺氧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鼹鼠，裸鼹鼠可以说是耐缺氧的哺乳动物冠军，因此是研究我们研究问题的理想模型，还有适度耐缺氧的近亲物种（达马拉兰和巨型赞比亚鼹鼠），以及耐缺氧的小鼠和大鼠。我们将调查以下短期目标/问题：哪种中枢神经系统信号机制控制非洲鼹鼠在发育过程中对缺氧的生理适应？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.在耐缺氧哺乳动物中有益活性氧（ROS）管理的基础是什么？这项研究将从根本上推动该领域的发展，揭示有利于调节生理和细胞能量学的机制的进化，以实现缺氧条件下的代谢稳态和生物体生存。我们将回答在发育背景下关于缺氧耐受性进化的重要基础研究问题。我们也可以告知生物医学领域的翻译研究，重点是在缺氧（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).