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

项目总结/摘要 氧气是人体中最常用的底物之一。当缺氧超过 人体的缓冲能力，对健康和生存有毁灭性的影响。例如三 美国五大死因之一是氧合受损的后果-心脏病， 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未满足的需求。通过揭示组织如何感知和适应 氧紧张，我们可以更好地理解和治疗这种受损的氧合条件。 线粒体电子传递链（ETC）消耗人体90%的氧气，同时提供 90%的ATP供应。有趣的是，能源生产对ETC的依赖程度在不同国家之间差异很大。 组织中剩余的氧气消耗来自几百个依赖氧气的反应， 以高度组织特异性的方式发生。此外，不同组织的缺氧耐受性差异很大。 在一个极端，大脑在没有氧气的情况下只能存活几分钟。在另一个极端， 肌肉可以在缺氧状态下存活数小时而不会造成永久性损伤。这种广泛的代谢灵活性 作为一个迷人的和有用的工具，研究适应机制缺氧。 传统上，比较生理学家从极端的生物体（例如， 海龟，威德尔海豹），可以在没有氧气的情况下生存数小时或数天。然而，这些战略 因为人类不具备这些独特的代谢途径或生理学， 有机体相反，我提出了一个现代的扭曲一个经典的问题-使用比较代谢跨越 最极端的组织，以确定氧气传感和适应途径。更具体地说，我建议改变 氧张力和（目的1）比较初级神经元与骨骼肌之间的生物能量学和代谢 肌管，（目标2）定义其各自的遗传和营养依赖性，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性通路。我们假设 代谢途径是神经元对骨骼肌管的缺血敏感性差异的基础。通过 了解这些差异，我们希望发现新的缺氧适应，并将其应用于疾病， 氧合受损，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.