Depressed but still functional: exploring the interplay between cellular and systemic adaptations of hypoxia-tolerant vertebrates

抑郁但仍有功能：探索耐缺氧脊椎动物的细胞和系统适应之间的相互作用

• 批准号: RGPIN-2015-04229
• 负责人: Pamenter, Matthew
• 金额: $ 2.11万
• 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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683048
• 关键词: Depressed; but; still; functional; exploring

This Discovery Program will take the novel approach of studying the brains of hypoxia-tolerant mammals to understand naturally evolved cellular strategies that protect brain cells against low oxygen stress (i.e., hypoxia). In particular we are interested in neuronal mechanisms of hypoxia-tolerance because neurons are the most hypoxia-sensitive cells in the body and therefore protective mechanisms against low oxygen stress will be most apparent in brain. At the cellular level, vertebrates rely on continuous oxygen delivery to facilitate aerobic energy production. Oxygen availability, however, is often limited by environmental factors, which in turn can ultimately impair energy production and survival. The key to tolerating hypoxia, both systemically and in the brain, is matching metabolic demand to energy supply. Vertebrates have evolved a range of adaptive strategies that contribute to this balance. These strategies can be grouped into two categories: i) increasing oxygen delivery to tissues, and ii) reducing systemic energy demand via metabolic rate depression. In mammals, this second mechanism is typically achieved via entry into torpor; however, my pilot studies in the hypoxia-tolerant naked mole rat demonstrate that this species undergoes robust metabolic depression in hypoxia but remains conscious, warm, and active. This is an important distinction as avoidance of torpor during hypoxia permits naked mole rats to forage, mate, and defend against predators in their natural hypoxic environment. These divergent strategies suggest fundamentally different adaptations to hypoxia, and in particular, suggest that naked mole rats may have evolved unique cellular and neuronal mechanisms of localized metabolic suppression that permit this animal to avoid torpor. However, despite the critical nature of oxygen homeostasis, we do not have a complete understanding of the cellular mechanisms that protect hypoxia-tolerant species in low oxygen environments. Particularly poorly understood are the mechanisms that protect brain cells during hypoxia in such tolerant species. This research program is designed to address this gap by determining 1) how synaptic function promotes metabolic suppression and neuroprotection in the hypoxia-tolerant brain, and 2) how cellular energetics are altered in hypoxia-tolerant species. This research will fundamentally advance the field by revealing naturally evolved mechanisms that beneficially modulate synaptic activity and cellular energetics to achieve metabolic homeostasis and neuronal survival in hypoxia. We will answer important basic research questions about the evolution of the hypoxia-tolerant brain in a developmental context. We will also inform important translation studies in biomedical fields focused on achieving neuroprotection in hypoxia (e.g., neonatal seizures, heart attack/stroke, sojourn/exercise at altitude, etc.).**

该发现计划将采用新方法研究耐缺氧哺乳动物的大脑，以了解保护脑细胞免受低氧应激（即缺氧）的自然进化的细胞策略。我们特别对耐缺氧的神经元机制感兴趣，因为神经元是体内对缺氧最敏感的细胞，因此针对低氧应激的保护机制在大脑中最为明显。 在细胞水平上，脊椎动物依靠持续的氧气输送来促进有氧能量的产生。然而，氧气的可用性往往受到环境因素的限制，这反过来又最终会损害能源生产和生存。耐受全身和大脑缺氧的关键是将代谢需求与能量供应相匹配。脊椎动物进化出了一系列有助于这种平衡的适应性策略。这些策略可分为两类：i）增加组织的氧气输送，ii）通过抑制代谢率来减少全身能量需求。在哺乳动物中，第二种机制通常是通过进入麻木状态来实现的。然而，我对耐缺氧裸鼹鼠的初步研究表明，该物种在缺氧时会经历强烈的代谢抑制，但仍保持意识、温暖和活跃。这是一个重要的区别，因为在缺氧期间避免麻木，使裸鼹鼠能够在自然缺氧环境中觅食、交配和防御捕食者。这些不同的策略表明对缺氧的根本不同的适应，特别是表明裸鼹鼠可能进化出了独特的局部代谢抑制的细胞和神经元机制，使这种动物能够避免麻木。然而，尽管氧稳态具有至关重要的性质，但我们对在低氧环境中保护耐缺氧物种的细胞机制还没有完全了解。人们对这种耐受性物种在缺氧期间保护脑细胞的机制知之甚少。 该研究项目旨在通过确定 1）突触功能如何促进耐缺氧大脑中的代谢抑制和神经保护，以及 2）如何改变耐缺氧物种的细胞能量学来解决这一差距。这项研究将从根本上推进该领域的发展，揭示自然进化的机制，有益地调节突触活动和细胞能量学，以实现代谢稳态和缺氧下神经元的存活。我们将回答有关发育背景下耐缺氧大脑进化的重要基础研究问题。我们还将为生物医学领域的重要转化研究提供信息，重点是实现缺氧状态下的神经保护（例如新生儿癫痫发作、心脏病发作/中风、高原逗留/运动等）。**