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.

摘要我正在寻求R35来解决O2中正确和左转的基本问题 血红蛋白解离曲线会影响人类的氧气转运。我还建议翻译密钥 在O2运输级联反应等特异性缺陷等疾病等疾病等疾病的结果 纤维化和/或充血性心力衰竭。我还提出了来自患者观察的反向翻译 关于O2递送和线粒体功能的更多基础研究。血红蛋白是前哨分子之一 负责“分子医学”的概念。该范式的一个核心要素是当 了解系统的基础分子成分的性能，然后更复杂的系统 现象将被解释。但是，关于血红蛋白和整个身体的“建立良好”概念 氧运输是矛盾的，值得进一步审查。标准教学是回应 缺氧，通过2,3-DPG的作用，O2血红蛋白解离曲线发生了急性右移。这 右移位促进了时机下氧气的卸载，并防止组织缺氧。然而， 通过进化来适应高海拔的物种剩下的O2血红蛋白解离曲线。这 表明在缺氧期间，在肺部加载更多的氧气并依靠低组织PO2维持 氧运输是解决缺氧挑战的更好的总体解决方案。这些不同的观察表明 与O2血红蛋白的转变有关 解离曲线和O2传递。在此应用中，我建议在梅奥诊所研究患者的情况很少 左右移动的血红蛋白变体是独特的“自然实验”，可以探索这些变体 权衡。使用重新利用的药物对健康志愿者的研究将增强患者研究 导致O2血红蛋白解离曲线的左右移位。这些研究的见解将是 翻译成临床人群。如果组织氧合在具有左移曲线的人类中保持 引起左移的药物可能对具有肺扩散限制的患者有用。这将允许 这样的患者可以通过较低的FIO2在肺部更好地氧合血液并减少呼吸。 同样，充血性心力衰竭的慢性组织缺氧可能会因引起的药物而降低 O2血红蛋白解离曲线的正确移动。 O2交付中的这些变化也可能会长期引起 肌肉线粒体功能的变化将表明后续翻译机械研究。 重要的是，由于我：1）访问独特的患者，2） 在药物重新定位方面的经验，3）心脏呼吸生理学专业知识和4）技术能力 基本上测量了O2的每个元素在人类中的运输级联。最后，因为R35 机制旨在促进PI的灵活性和冒险，这是追求这个大问题和的理想选择 我提出的实验方法将带来双向翻译机会。