Variant Hemoglobin and Cardiorespiratory Regulation in Humans

人类变异血红蛋白和心肺调节

• 批准号: 10532798
• 负责人: MICHAEL J JOYNER
• 金额: $ 80.62万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-19 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532798
• 关键词: Acute; Address; Affect; Affinity; Air; Altitude; Binding; Blood; CCL4 gene; Chronic; Clinic; Clinical; Complex; Congestive Heart Failure; Defect; Disease; Dissociation; Educational process of instructing; Elements; Evolution; Hemoglobin; Human; Hypoxia; Left; Life; Lung; Measures; Mitochondria; Molecular; Molecular Medicine; Muscle Mitochondria; Nature; Oxygen; Patients; Pharmaceutical Preparations; Physiological; Physiology; Population; Process; Property; Pulmonary Diffusing Capacity; Qualifying; Regulation; Risk Taking; Sentinel; System; Tissues; Translating; Translations; Variant; Work of Breathing; design; drug repurposing; experience; experimental study; flexibility; follow-up; healthy volunteer; idiopathic pulmonary fibrosis; insight; oxygen transport; response; tissue oxygenation; translational potential

Abstract I am seeking an R35 to address the fundamental issue of how right and left shifts in the O2 hemoglobin dissociation curve influence oxygen transport in humans. I am also proposing to translate key findings to the treatment of diseases with specific defects in the O2 transport cascade like idiopathic pulmonary fibrosis and/or congestive heart failure. I am also proposing reverse translation from observations in patients to more basic studies on O2 delivery and mitochondrial function. Hemoglobin is one of the sentinel molecules responsible for the concept of “molecular medicine”. A central element of this paradigm is that when the properties of the foundational molecular components of a system are understood, then more complex systems phenomenon will be explained. However, “well-established” concepts about hemoglobin and whole body oxygen transport are contradictory and deserve further scrutiny. The standard teaching is that in response to hypoxia, there is an acute right shift in the O2 hemoglobin dissociation curve via the actions of 2,3-DPG. This right shift facilitates the off-loading of oxygen at the tissues and protects against tissue hypoxia. However, species adapted to high altitude via evolution have left shifted O2 hemoglobin dissociation curves. This suggests that during hypoxia, loading more oxygen at the lung and relying on low tissue PO2 to maintain oxygen transport is a better overall solution to the challenge of hypoxia. These divergent observations indicate there is a complex set of context-dependent physiological “trade-offs” associated with shifts in O2 hemoglobin dissociation curve and O2 delivery. In this application, I propose studying patients at the Mayo Clinic with rare right and left shifted hemoglobin variants as unique “experiments in nature” that will allow exploration of these trade-offs. Patient studies will be augmented with studies in healthy volunteers using repurposed drugs that cause right and left shifts of the O2 hemoglobin dissociation curve. Insight from these studies will then be translated to clinical populations. If tissue oxygenation is maintained in humans with left shifted curves, then drugs that cause a left shift might be useful in patients with pulmonary diffusion limitation. This would permit such patients to better oxygenate their blood at the lung with a lower FiO2 and reduced work of breathing. Likewise, there is chronic tissue hypoxia in congestive heart failure that might be reduced by drugs that cause a right shift in the O2 hemoglobin dissociation curve. These changes in O2 delivery might also evoke long term changes in muscle mitochondrial function that will suggest follow-up reverse translation mechanistic studies. Importantly, I am uniquely qualified to explore these ideas because of my: 1) access to unique patients, 2) experience in drug re-purposing, 3) expertise in cardiorespiratory physiology, and 4) technical ability to measure essentially every element of the O2 transport cascade in humans. Finally, because the R35 mechanism is designed to promote flexibility and risk taking by the PI, it is ideal to pursue this big issue and the bi-directional translational opportunities that will flow from the experimental approach I have proposed.

摘要我正在寻找一台R35来解决O2中如何左右移动的根本问题 血红蛋白解离曲线影响氧在人体内的转运。我还提议翻译KEY 特发性肺组织氧转运级联缺陷疾病的治疗研究 纤维化和/或充血性心力衰竭。我还建议从患者的观察中进行反向翻译 更多关于氧气输送和线粒体功能的基础研究。血红蛋白是前哨分子之一。 负责“分子医学”的概念。这一模式的一个核心要素是，当 了解系统的基本分子组件的性质，然后了解更复杂的系统 这一现象将被解释。然而，关于血红蛋白和全身的“成熟”概念 氧气的运输是相互矛盾的，值得进一步研究。标准的教学是为了回应 低氧时，在2，3-DPG的作用下，O2血红蛋白解离曲线急剧右移。这 向右移位有助于减轻组织中的氧气负荷，保护组织免受缺氧。然而， 通过进化适应高海拔的物种，O2血红蛋白解离曲线左移。这 提示在低氧期间，肺内的氧气负荷较多，依靠低组织氧分压来维持 氧气运输是应对低氧挑战的更好的整体解决方案。这些不同的观察表明 与氧合血红蛋白的变化相关的一系列复杂的生理“权衡”与环境相关 解离曲线和氧气输送。在这个应用程序中，我建议研究梅奥诊所的患者，他们患有罕见的 右移和左移的血红蛋白变体作为独特的“自然界的实验”，将允许探索这些 权衡取舍。患者研究将增加对健康志愿者的研究，使用重新调整用途的药物 引起氧合血红蛋白解离曲线左右移。从这些研究中获得的见解将是 转化为临床人群。如果在曲线左移的人类中维持组织氧合，那么 引起左移位的药物可能对肺弥散受限的患者有用。这将允许 这类患者在低氧血氧饱和度和减少呼吸功的情况下，可以在肺部更好地给血液充氧。 同样，在充血性心力衰竭中存在慢性组织缺氧，这种情况可能通过药物的作用而减轻。 氧合血红蛋白解离曲线右移。氧气输送的这些变化也可能引起长期的 肌肉线粒体功能的变化将提示后续的反向翻译机制研究。 重要的是，我是唯一有资格探索这些想法的人，因为我：1)接触独特的患者，2) 药物再利用经验，3)心肺生理学专业知识，4)技术能力 测量氧气在人体内传输的每一个元素。最后，因为R35 机制旨在促进私人投资公司的灵活性和风险承担，这是追求这个大问题和 将从我提出的试验性方法中产生的双向翻译机会。