Redesigning a Neuron's Breath: A Modern Twist to Classical Oxygen Biology

项目摘要/摘要 氧气是人体内最常用的底物之一。当缺氧量超过 人体的缓冲能力，对健康和生存都有毁灭性的影响。例如，三个 在美国的五大死因中，心脏病是由氧合受损引起的。 呼吸道疾病和中风。事实上，仅在美国，每年就有超过40万人患有中风， 留下了对新疗法的巨大需求，尚未得到满足。通过揭示组织如何感知和适应 氧分压，我们可以更好地了解和治疗这种氧合受损的情况。 线粒体电子传输链(ETC)消耗人体90%的氧气，同时提供 90%的ATP供应。有趣的是，对ETC能源生产的依赖程度在很大程度上各不相同 纸巾。剩余的氧气消耗来自数百个氧依赖反应，这些反应也 以高度组织特异性的方式发生。此外，不同组织对低氧的耐受性差异很大。 在一个极端情况下，大脑在没有氧气的情况下只能存活几分钟。在另一个极端，骨瘦如柴 肌肉可以在几个小时的缺氧中存活下来，而不会受到永久性的损伤。如此广泛的新陈代谢灵活性 是研究低氧适应机制的一个有趣而有用的工具。 传统上，比较生理学家从极端有机体(例如 海龟、威德尔海豹)，可以在没有氧气的情况下一次存活数小时或数天。然而，这些战略 很少是可翻译的，因为人类没有这些独特的代谢途径或生理 有机体。相反，我提出了一个经典问题的现代转折？？使用比较新陈代谢。 识别氧气感应和适应途径的最极端的组织。更具体地说，我建议改变 氧分压和(目标1)比较初级神经元和骨骼之间的生物能量学和代谢 肌管，(目标2)定义它们各自的遗传和营养依赖关系，并(目标3)使用这些见解 在中风小鼠模型中操纵脑缺氧的适应途径。我们假设这种独一无二的 代谢途径是神经元和骨骼肌管对缺血敏感性差异的基础。通过 了解这些差异，我们希望发现新的低氧适应并将其应用于 氧合功能受损，如缺血性中风。

PROJECT SUMMARY/ABSTRACT Oxygen is one of the most used substrates in the human body. When oxygen deprivation exceeds the buffering capacity of the human body, there are devastating effects on health and survival. For example, three of the five leading causes of death in the US are a consequence of impaired oxygenation – heart disease, respiratory disease and stroke. Indeed, over 400,000 individuals suffer from a stroke each year in the US alone, leaving a great unmet need for new therapies. By uncovering how tissues sense and adapt to variations in oxygen tensions, we can better understand and treat such conditions of impaired oxygenation. The mitochondrial electron transport chain (ETC) consumes 90% of the body's oxygen, while providing 90% of the ATP supply. Interestingly, the reliance on the ETC for energy production varies substantially across tissues. The remaining oxygen consumption arises from several hundred oxygen-dependent reactions that also occur in a highly tissue-specific manner. Moreover, hypoxia tolerance varies drastically across different tissues. At one extreme, the brain can only survive for several minutes without oxygen. At the other extreme, skeletal muscle can survive several hours of anoxia without permanent damage. This wide range of metabolic flexibilities across the human body serves as a fascinating and useful tool to study adaptive mechanisms for hypoxia. Traditionally, comparative physiologists have drawn inspiration from extreme organisms (e.g. painted turtles, Weddell seals) that can survive without oxygen for hours or days at a time. However, these strategies are rarely translatable as humans do not possess the unique metabolic pathways or physiology of these organisms. Instead, I propose a modern twist to a classical problem – the use of comparative metabolism across the most extreme tissues to identify oxygen sensing and adaptive pathways. More specifically, I propose varying oxygen tensions and (Aim 1) comparing the bioenergetics and metabolism between primary neurons vs. skeletal myotubes, (Aim 2) defining their respective genetic and nutrient dependencies and (Aim 3) using these insights to manipulate adaptive pathways for cerebral hypoxia in a mouse model of stroke. We hypothesize that unique metabolic pathways underlie the differences in ischemia sensitivity of neurons vs. skeletal myotubes. By understanding such differences, we hope to uncover novel hypoxia adaptations and apply them to disorders of impaired oxygenation such as ischemic stroke.